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Human African trypanosomiasis (HAT), a parasitic protozoal disease, is caused primarily by two subspecies of Trypanosoma brucei. HAT is a re-emerging disease and currently threatens millions of people in sub-Saharan Africa. Many affected people live in remote areas with limited access to health services and, therefore, rely on traditional herbal medicines for treatment.
A molecular docking study has been carried out on phytochemical agents that have been previously isolated and characterized from Nigerian medicinal plants, either known to be used ethnopharmacologically to treat parasitic infections or known to have in-vitro antitrypanosomal activity. A total of 386 compounds from 19 species of medicinal plants were investigated using in-silico molecular docking with validated Trypanosoma brucei protein targets that were available from the Protein Data Bank (PDB): Adenosine kinase (TbAK), pteridine reductase 1 (TbPTR1), dihydrofolate reductase (TbDHFR), trypanothione reductase (TbTR), cathepsin B (TbCatB), heat shock protein 90 (TbHSP90), sterol 14α-demethylase (TbCYP51), nucleoside hydrolase (TbNH), triose phosphate isomerase (TbTIM), nucleoside 2-deoxyribosyltransferase (TbNDRT), UDP-galactose 4′ epimerase (TbUDPGE), and ornithine decarboxylase (TbODC).
This study revealed that triterpenoid and steroid ligands were largely selective for sterol 14α-demethylase; anthraquinones, xanthones, and berberine alkaloids docked strongly to pteridine reductase 1 (TbPTR1); chromenes, pyrazole and pyridine alkaloids preferred docking to triose phosphate isomerase (TbTIM); and numerous indole alkaloids showed notable docking energies with UDP-galactose 4′ epimerase (TbUDPGE). Polyphenolic compounds such as flavonoid gallates or flavonoid glycosides tended to be promiscuous docking agents, giving strong docking energies with most proteins.
This in-silico molecular docking study has identified potential biomolecular targets of phytochemical components of antitrypanosomal plants and has determined which phytochemical classes and structural manifolds likely target trypanosomal enzymes. The results could provide the framework for synthetic modification of bioactive phytochemicals, de novo synthesis of structural motifs, and lead to further phytochemical investigations.
Author Summary
Traditional herbal medicine continues to play a key role in health, particularly in remote areas with limited access to "modern medicines". Many plants are used in traditional Nigerian medicine to treat parasitic diseases. While many of these plants have shown notable activity against parasitic protozoa, in most cases the mode of activity is not known. That is, it is not known what biochemical entities are being targeted by the plant chemical constituents. In this work, we have carried out molecular docking studies of known phytochemicals from Nigerian medicinal plants used to treat human African trypanosomiasis (sleeping sickness) with known biochemical targets in the Trypanosoma brucei parasite. The goals of this study were to identify the protein targets that the medicinal plants are affecting and to discern general trends in protein target selectivity for phytochemical classes. In doing so, we have theoretically identified strongly interacting plant chemicals and their biomolecular targets. These results should lead to further research to verify the efficacy of the phytochemical agents as well as delineate possible modifications of the active compounds to increase potency or selectivity.
Citation: Setzer WN, Ogungbe IV (2012) In-silico Investigation of Antitrypanosomal Phytochemicals from Nigerian Medicinal Plants. PLoS Negl Trop Dis 6(7): e1727. https://doi.org/10.1371/journal.pntd.0001727
Editor: Kiyoshi Kita, University of Tokyo, Japan
Received: February 20, 2012; Accepted: May 26, 2012; Published: July 24, 2012
Copyright: © 2012 Setzer, Ogungbe. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have indicated that no funding was received for this work.
Competing interests: The authors have declared that no competing interests exist.
Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by the single-celled kinetoplastid parasites, Trypanosoma brucei, which are transmitted to humans by infected tsetse flies (Glossina spp.). Two sub-species of T. brucei (rhodesiense and gambiense) cause the two different forms of the disease. T. b. rhodesiense is found in southern and eastern Africa while T. b. gambiense is found in the western, central and some parts of eastern Africa. T. b. gambiense now accounts for about 90% of all reported cases of sleeping sickness. A third subspecies, T. b. brucei, does not cause HAT because of its susceptibility to lysis by human apolipoprotein L1 [1].
Current chemotherapies of HAT are directed either to the early or late stages of the disease. All the clinically available HAT chemotherapeutic drugs have been noted to be ineffective, and they also have severe side-effects. The only drug candidate in clinical trials for the treatment of HAT is the nitroimidazole fexinidazole. Fexinidazole is currently in clinical study for the treatment of the late stage form of HAT [2], [3]. It is worth noting that the number of reported cases of HAT fell in the past decade, and it has also been suggested that a possible elimination of the disease might be in sight [4]. This is a very delightful development for this "neglected" tropical disease, and it is our hope that continued research into new and effective chemotherapy against HAT remains an integral part of public health initiatives in endemic communities.
Medicinal plants from Nigeria's lush rainforest, as well as her very diverse montane and savanna vegetation, continue to play a vital role in her healthcare system. For tens of millions of Nigerians, indigenous traditional medicine is the major – and sometimes the only – access to pharmacological agents [5]. There have been several published reports on the biological activity of Nigerian plants, but most of the bioactive components of those plants have not been characterized. However, the country's big and loosely-regulated traditional medicine industry continues to promote the efficacy of extracts and concoctions made from most of the plants. A number of Nigerian plants have been used traditionally in West Africa to treat protozoal infections and many of these have shown in-vitro antiprotozoal activity (Table S1).
Several T. brucei protein targets have been identified and experimentally validated [6]. In addition to validated targets, several potential targets have been predicted in silico [7]. For a recent review of phytochemical agents that show activities against parasitic protozoans and protozoan biochemical targets, see [8], [9]. Some of the potential T. brucei drug targets that we considered in this work include adenosine kinase [10], pteridine reductase 1 [11], dihydrofolate reductase [12], trypanothione reductase [13], cathepsin B [14], heat shock protein 90 [15], as well as sterol 14α-demethylase (CYP51) [16], nucleoside hydrolase [17], triose phosphate isomerase [18], nucleoside 2-deoxyribosyltransferase [19], UDP-galactose 4′ epimerase [20] and ornithine decarboxylase [21]. In this computational study, we have evaluated the interaction of compounds that were isolated from some antitrypanosomal Nigerian medicinal plants (Table S1) against potential protein drug targets in Trypanosoma brucei for which X-ray crystal structures were available from the Protein Data Bank (PDB). We strove to address the questions of which phytochemical agents might be responsible for the observed antitrypanosomal activity and what are the likely targets of those phytochemicals. In doing so, we hope to identify particular classes of phytochemical agents that can be exploited for antiparasitic chemotherapy.
Protein-ligand docking studies were carried out based on the crystal structures of rhodesain (PDB 2p7u, [22] and PDB 2p86 [23]), T. brucei adenosine kinase, TbAK (PDB 2xtb and PDB 3otx [24]), T. brucei pteridine reductase 1, TbPTR1 (PDB 3jq7 [25]), T. brucei dihydrofolate reductase, TbDHFR (PDB 3rg9 and PDB 3qfx [26]), T. brucei trypanothione reductase, TbTR (PDB 2wow, [27]), T. brucei cathepsin B, TbCatB (PDB 3hhi [28]), T. brucei heat shock protein 90, TbHSP90 (PDB 3omu [29] and PDB 3opd [30]), T. brucei sterol 14α-demethylase, TbCYP51 (PDB 3gw9 [16]), T. brucei nucleoside hydrolase, TbNH (PDB 3fz0 [31]), T. brucei triosephosphate isomerase, TbTIM (PDB 1iih, PDB 6tim [32], and PDB 4tim [33]), T. brucei nucleoside 2-deoxyribosyltransferase, TbNDRT (PDB 2a0k, PDB 2f64, and PDB 2f67 [19]), T. brucei UDP-galactose 4′-epimerase, TbUDPGE (PDB 1gy8 [20]), and T. brucei ornithine decarboxylase, TbODC (PDB 1f3t [34], PDB 1njj [35], and PDB 1qu4 [21]). All solvent molecules and the co-crystallized ligands were removed from the structures. Molecular docking calculations for all compounds with each of the proteins were undertaken using Molegro Virtual Docker v. 4.3 [36], [37], with a sphere large enough to accommodate the cavity centered on the binding sites of each protein structure in order to allow each ligand to search. If a co-crystallized inhibitor or substrate was present in the structure, then that site was chosen as the binding site. If no co-crystallized ligand was present, then suitably sized cavities were used as potential binding sites. Standard protonation states of the proteins based on neutral pH were used in the docking studies. The protein was used as a rigid model structure; no relaxation of the protein was performed. Assignments of charges on each protein were based on standard templates as part of the Molegro Virtual Docker program; no other charges were set. Each ligand structure was built using Spartan '08 for Windows [38]. The structures were geometry optimized using the MMFF force field [39]. Flexible ligand models were used in the docking and subsequent optimization scheme. As a test of docking accuracy and for docking energy comparison, co-crystallized ligands were re-docked into the protein structures. Different orientations of the ligands were searched and ranked based on their energy scores. The RMSD threshold for multiple cluster poses was set at <1.00 Å. The docking algorithm was set at maximum iterations of 1500 with a simplex evolution population size of 50 and a minimum of 30 runs for each ligand. Each binding site of oligomeric structures was searched with each ligand. The lowest-energy (strongest-docking) poses for each ligand in each protein target are summarized in Tables S2–S20.
Results and Discussion
Acacia nilotica
Phytochemical studies of Acacia nilotica [40]–[45] have shown an abundance of polyphenolic compounds (Table S2), including hydrolyzable tannins, flavonoid gallates, and flavonoid glycosides. Although these polyphenolics are notorious for being promiscuous protein complexing agents and they do show relatively strong docking to all proteins investigated in this study, some selectivity can be seen. Thus, for example, 1,3-digalloylglucose showed docking selectivity for TbUDPGE, 3′,5-digalloylcatechin was selective for TbAK, and 3′,7-digalloylcatechin selectively docked with TbNH and was the strongest binding ligand for that protein (−44.2 kcal/mol). 5,7-Digalloylcatechin was the strongest binding ligand for TbPTR1 (−42.7 kcal/mol) and 4′,7-digalloylcatechin was the strongest binding ligand for TbODC (−41.4 kcal/mol). A number of these polyphenolic ligands showed strong docking interactions with TbAK, TbPTR1, TbCYP51, TbNH, and TbUDPGE, and interactions with these protein targets may be responsible for the antitrypanosomal activity of A. nilotica [46]. The docking study suggests that rhodesain, TbDHFR, TbTR, TbCatB, and TbHSP90 are not targets for A. nilotica phytochemicals.
Ageratum conyzoides
Ageratum conyzoides extracts have been dominated by flavonoids and chromanes (Table S3) [40], [47]–[49]. 5,6-Dimethoxy-2-isopropylbenzofuran, 6,7-dimethoxy-2-methyl-2-(2-methyl-1-propanone)-3-chromene, 6-acetyl-2,2-dimethylchroman, and O-methylenececalinol exhibited selectivity for TbTIM with docking energies comparable to the co-crystallized ligand, 3-phosphoglyceric acid (−21.6 kcal/mol). The flavonoid 3′,4′,5,5′,6,8-hexamethoxyflavone, on the other hand, showed selective docking to TbPTR1 and TbUDPGE. Nour and co-workers [49] have examined the antitrypanosomal activities of several methylated flavonoids and a chromene from A. conyzoides. The flavonoids all have similar antitrypanosomal activities with IC50 values ranging from 3.0 to 6.7 µg/mL. The chromene, O-methylencedalinol, on the other hand, was much less active (IC50 = 78.4 µg/mL). The docking energies for many of the protein targets was much more negative (stronger docking) for the flavonoids than for the chromene. Thus, for example, there is good correlation between log(IC50) and docking energies of the ligands with TbPTR1 or with TbUDPGE (R2 = 0.712 and 0.751, respectively).
Annona senegalensis
Compounds isolated from Annona senegalensis include annonaceous acetogenins, diterpenoids, and sesquiterpenoids, and aporphine alkaloids (Table S4) [40], [50]–[53]. The acetogenins (annogalene, annonacin, annonacin A, annosenegalin, and senegalene) are probably responsible for the antitrypanosomal activity of the plant [54], [55]. These compounds show a propensity for docking with TbAK, TbCYP51, and TbUDPGE. The acetogenins are very flexible with a great deal of conformational mobility. Nevertheless, docking with these protein targets is largely hydrophobic. Key interactions of the acetogenins with TbAK include Phe337, Gly298, Asn295, Asn67, and Gly296. Additionally, the acetogenin annogalene is one of the best binding ligands for TbDPGE (−42.9 kcal/mol).
Bridelia ferruginea
Bridelia ferruginea has been phytochemically characterized with polyphenolic and triterpenoid constituents (Table S5) [40], [56]. The flavonoids delphinidin and ferrugin showed docking selectivity for TbPTR1. The tannin epigallocatechin(7→4′)gallocatechin showed notably strong docking with TbCYP51. Although they are relatively weak docking ligands, the triterpenoids friedelin and taraxerol docked selectively with TbUDPGE.
Carapa procera
Limonoids are characteristic phytochemicals of the Meliaceae, including Carapa procera (Table S6) [40], [57], and numerous limonoids have exhibited antiprotozoal activities [58]–[62]. Six of the eleven C. procera limonoids showed notably strong docking with TbCYP51 (docking energies<−26 kcal/mol). A similar trend was noted for docking of Khaya limonoids (see below). Carapolides A, B, and C showed particularly strong docking with docking energies of −31.8, −29.3, and −28.5 kcal/mol, respectively; comparable to the docking energy of the co-crystallized ligand, N-[(1R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide [16] (−28.6 kcal/mol), for this protein. The limonoids all dock with TbCYP51 near the heme cofactor (Fig. 1). In addition, preferential docking of individual limonoids with other protein targets include: mexicanolide with TbAK, 3β-isobutyroloxy-1-oxomeliac-8(30)-enate with TbPTR1, and evodulone with TbCatB. We conclude, therefore, that T. brucei sterol 14α-demethylase, TbCYP51, is a protein target of C. procera limonoids.
The docked ligand is carapolide A (stick figure). The co-crystallized ligand is shown as a green wire figure and the heme cofactor is shown as a space-filling structure.
Enantia chlorantha
Enantia chlorantha is dominated by aporphine and berberine alkaloids (Table S7) [40], [63], [64]. E. chlorantha aporphine alkaloids seem to show a propensity for docking with TbPTR1 or with TbUDPGE while the berberine alkaloids showed selectivity for TbPTR1. Both pseudocolumbamine and pseudopalmatine docked with TbPTR1 with docking energies (−27.5 kcal/mol) comparable to the co-crystallized ligand, 6-phenylpteridine-2,4,7-triamine [25] (−27.6 kcal/mol). These planar alkaloids dock into the active site by way of hydrophobic interactions with the NADP+ cofactor and a hydrophobic pocket formed by Phe97, Met163, Cys168, Pro210, Trp221, and Leu209 (Fig. 2). Liriodenine and columbamine docked selectively to TbTIM with docking energies lower (−24.0 and −24.7 kcal/mol) than the co-crystallized ligand, 3-phosphoglyceric acid [32] (−21.6 kcal/mol). These nearly planar alkaloids are known also to be DNA intercalators and topoisomerase inhibitors [65].
Top: Lowest-energy docking poses of pseudocolumbamine (green stick figure) and pseudopalmatine (yellow stick figure) in the crystal structure. The NADP+ cofactor is shown as a space-filling structure. Bottom: Lowest-energy docking poses of laxanthone II (brown stick figure) and laxanthone III (dark green stick figure) in the same crystal structure.
Garcinia kola
Polyphenolic compounds, flavonoids, biflavonoids, etc., have been isolated and identified from Garcinia kola (Table S8) [40], [66]. G. kola biflavonoids docked favorably with TbAK and TbODC. The biflavonoids do not dock at the adenosine binding sites of TbAK, but rather in a pocket between the two sites bounded by residues Asn222, Gly298, Ala297, Thr264, Asp266, Glu225, Arg132, and Asn195 (see Fig. 3). Likewise, biflavonoid docking with TbODC does not occur at the ornithine/putrescine binding site or the geneticin binding site, but rather in a pocket bounded by Asp243, Asp385, Val335, Asp332, Ala334, Ala244, and Arg277 (Fig. 4). This would suggest that if G. kola biflavonoids inhibit either TbAK or TbODC, they act as allosteric inhibitors of these proteins. The two tocotrienols garcinal and garcinoic acid, on the other hand, docked more favorably with TbUDPGE. Key interactions of the tocotrienols with the protein are hydrogen-bonding of the phenolic –OH of the ligands with Pro253 and Phe255, hydrogen-bonding of the carbonyl group of the ligand side chains with Arg268, hydrogen-bonding of the pyran ring oxygen atom with Arg235, face-to-face π – π interactions of the ligand aromatic rings with Phe255, and hydrophobic interactions of the tocotrienol ligands with Leu222, His221 and the NAD cofactor (Fig. 5 top). The prenylated benzophenone kolanone docked very strongly with TbNH (docking energy = −37.1 kcal/mol) in the nucleoside binding site (Fig. 6), a hydrophobic pocket bounded by Trp80, Phe178, Asn171, Trp205, and Val277, with additional hydrogen-bonding with Asn171.
The docked poses are the biflavonoids GB1 (turquoise), GB1a (magenta), GB2 (yellow), and garciniflavanone (white). The co-crystallized ligand, bis(adenosine)-5′-pentaphosphate, is shown as a green wire figure.
The docked poses are the biflavonoids GB1a (magenta), GB2 (yellow), GB3 (green) and kolaflavanone (brown). The co-crystallized ligands are geneticin (green wire figure) and pyridoxylphosphate/d-ornithine (yellow wire figure).
Top: Lowest-energy docked poses of garcinal (purple stick figure) and garcinoic acid (yellow stick figure) showing key hydrogen-bonding and hydrophobic interactions. The NAD cofactor is shown as a space-filling structure; hydrogen bonds are depicted as blue dashed lines. Bottom: Lowest-energy docked pose of 3-O-acetylkhayalactone (green stick figure) in the same crystal structure.
The lowest energy docking poses of kolanone (green), oruwacin (magenta), and dehydroepoxymethoxygaertneroside (yellow) are shown in the active site.
Khaya ivorensis and Khaya senegalensis
The phytochemical compositions of Khaya ivorensis [67] and K. senegalensis [58], [68]–[72], like other members of the Meliaceae, are characterized by limonoids [40]. Many of the Khaya limonoids showed markedly strong docking to TbAK as well as TbCYP51 (see Table S9). Of particular note, 3-O-acetylkhayalactone strongly docked with TbAK, TbDHFR, and TbUDPGE (−31.6, −32.2, and −34.2 kcal/mol, respectively). This ligand docked in the same site in TbAK as the Garcinia biflavonoids (above), but in a different position in TbUDPGE (Fig. 5 bottom). Important hydrogen-bonding interactions of 3-O-acetylkhayalactone with TbUDPGE are with residues Glu214, Ser219, Leu102, Thr220, and His221. 3-O-Acetylkhayalactone docked in the active site of TbDHFR in the same general location as the co-crystallized ligand (Fig. 7). In addition, the docking energy of 3-O-acetylkhayalactone (−32.2 kcal/mol) was lower than either of the co-crystallized ligands, 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine (pyrimethamine) and 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine [26] (−22.7 and −30.1 kcal/mol, respectively). In general, the Khaya limonoids showed weak or no docking with TbNH, TbTIM, or TbNDRT.
The docked structure is 3-O-acetylkhayalactone (magenta). The co-crystallized ligand, pyrimethamine, is shown as a green wire figure and the NADPH cofactor as a space-filling structure.
Lawsonia inermis
The sterols and triterpenoids [40] from Lawsonia inermis showed preferential docking to TbCYP51 (T. brucei sterol 14α-demethylase) (Table S10). This is perhaps not surprising since the normal substrates for this enzyme are sterols. The laxanthones from L. inermis showed preferential docking to TbPTR1 with docking energies comparable to the co-crystallized ligand. In addition, they docked in the same positions and orientations as pseudocolumbamine and pseudopalmatine from Enantia chlorantha (see above and Fig. 2).
Morinda lucida
Anthraquinones dominate the phytochemistry of Morinda lucida [40], [73], [74], along with triterpenoid acids [75] (see Table S11). Anthraquinones, as a class, demonstrated significant docking affinity for TbPRT1 and TbTIM (Fig. 8). Anthraquinones are also known to be DNA intercalators and topoisomerase inhibitors [76]. The triterpenoid acids oleanolic acid and ursolic acid showed notable docking energies with TbCYP51 (see above). The phenylpropanoid oruwacin docked very strongly to TbPTR1 (docking energy = −32.4 kcal/mol) and TbNH (docking energy = −31.6 kcal/mol, Fig. 6).
The docked structures are the lowest-energy docking poses of the strongly docking M. lucida anthraquinones (2-formyl-3-hydroxyanthaquinone, 2-formylanthraquinone, 2-hydroxy-3-hydroxymethyl-anthraquinone, nordamnacanthal, rubiadin, and soranjidiol) in the active site of the protein.
Morinda morindoides
The phytochemistry of Morinda morindoides [40] is dominated by flavonoid glycosides [77] and phenylpropanoid-conjugated iridoid glycosides [78] (Table S12). Of these, epoxygaertneroside and morindaoside were selectively strongly binding ligands for TbAK, and morindaoside also docked strongly to TbPTR1. A number of gaertneroside derivatives showed docking selectivity for TbDHFR (see Table S12), while dehydroepoxymethoxygaertneroside docked very strongly with TbNH, occupying the nucleoside binding site (Fig. 6) with the same hydrophobic interactions as kolanone and oruwacin (above). It is unlikely that these glycosides will remain intact in vivo, and hydrolysis may be necessary for absorption and general bioavailability [79]. Of the flavonoid aglycones from M. morindoides, apigenin, chrysoeriol, kaempferol, quercetin, and ombuin selectively docked with TbPTR1.
Nauclea latifolia
Phytochemical investigations of Nauclea latifolia have revealed numerous indole alkaloids [40], [80], [81] (Table S13). The alkaloid glycosides 10-hydroxystrictosamide, cadambine, dihydrocadambine, and tetrahydrodesoxycordifoline showed notably strong docking to TbUDPGE, whereas non-glycosylated alkaloids showed preferential docking with TbPTR1and/or TbAK. 10-Hydroxyangustine, angustine, naucleamide B, and naucletine, in particular, docked more strongly with TbPTR1 than the co-crystallized ligand, 6-phenylpteridine-2,4,7-triamine [25] (docking energy = −27.6 kcal/mol).
Newbouldia laevis
T. brucei triosephosphate isomerase, TbTIM, is the likely protein target for the phytochemical agents of Newbouldia laevis. Both furanonaphthoquinones [82], [83] and pyrazole alkaloids [84], [85] from this plant showed remarkable selective affinity for this protein (Table S14). The monomeric furanonaphthoquinone ligands all occupy the same site with hydrogen bonding of the furan oxygen and C(9) carbonyl oxygen to Lys313; C(4) carbonyl oxygen with Ser513 and Val514; a van der Waals surface provided by Val533, Gly534, Gly535; and a hydrophobic pocket to accommodate the isopropenyl moiety provided by Ile472, Gly512, and Leu532 (see Fig. 9). Similarly, the pyrazole alkaloid 4′-hydroxywithasomnine has key hydrogen-bonding interactions between the pyrazole ring nitrogens and Ser513 and Val514. The aromatic ring lies in the hydrophobic pocket made up of Ile472 and Leu532, and there is an additional hydrogen-bonding interaction between the phenolic –OH group and His395 (Fig. 9).
The lowest-energy docking poses of 6-hydroxydehydroiso-α-lapachone (left) and 4′-hydroxywithasomnine (right) in the active site are shown. Hydrogen-bonding interactions are indicated by blue dashed lines.
Physalis angulata
Withanolide triterpenoids, abundant components of Physalis angulata [40], [86]–[88], generally showed preferential docking to T. brucei sterol 14α-demethylase, TbCYP51 (Table S15). This is consistent with the docking of L. inermis triterpenoids and steroids, C. procera and Khaya limonoids (see above). Five of the withanolides, 14-hydroxyixocarpanolide, physagulin J, physagulin L, withangulatin H, and withangulatin I, docked more strongly to TbCYP51 than the co-crystallized ligand [16]. Three withanolides, physagulin A, physagulin L′, and withangulatin A, docked more strongly into TbODC than the co-crystallized ligand (pyridoxal 5′-phosphate) for that protein [34]. The pyrrolidine alkaloid, phygrine, docked with TbTIM preferentially.
Picralima nitida
Picralima nitida glycosylated coumestans [89] showed strong binding to most of the protein targets, except for TbNDRT (Table S16). They are, for example, along with Acacia nilotica flavonoid gallates, the only ligands that dock to rhodesain with docking energies comparable to the co-crystallized ligand. Of the ligands examined in this work, coumestan 2 is the strongest-binding ligand for TbAK (−44.1 kcal/mol) and TbUDPGE (−43.7 kcal/mol). The corresponding aglycones, 4, 5, and 6, however, were selective for TbPTR1 as well as TbUDPGE.
Prosopis africana
The phytochemistry of Prosopis africana is characterized by piperidine alkaloids (Table S17) [40], [90]. These ligands exhibited similar docking energies with all protein targets, owing presumably to the small, flexible nature of the compounds. They did, however, show slightly better affinity for TbAK.
Rauwolfia vomitoria
Phytochemical investigations of Rauwolfia vomitoria have revealed this plant to be replete with indole alkaloids (Table S18) [40], [91], [92]. The structural diversity of these indole alkaloids seems to defy targeting any one particular protein. There are some notable docking results, however. 3-Epirescinnamine docked with TbPRT1 and with TbODC more strongly than the co-crystallized ligands, 6-phenylpteridine-2,4,7-triamine [25] and putrescine [34], respectively. Isoreserpiline, raumitorine, and rauvanine also docked strongly to TbPTR1. Ajmalimine, isoreserpiline, rauvomitine, and serpenticine had remarkable docking energies with TbNH. The trimethoxybenzoyl and trimethoxycinnamyl esters, renoxydine, rescidine, rescinnamine, reserpine, along with methyl 3,4-dimethoxybenzoylreserpate, were all excellent ligands for TbUDPGE, with docking energies comparable to uridine-5′-diphosphate, the co-crystallized ligand [20]. Of these, renoxydine, rescidine, and reserpine, along with neonorreserpine, docked strongly to TbCYP51.
Securidaca longipedunculata
Cinnamate esters from Securidaca longipedunculata [40] showed selective docking to TbTIM while S. longipedunculata xanthones [40], [93] had a docking preference for TbPTR1. Both of these protein targets have relatively small binding sites, which are more suitable for the small ligands (Fig. 10). The xanthones also docked relatively strongly with TbUDPGE. The S. longipedunculata indole alkaloids dehydroelymoclavine and alkaloid A [94] docked strongly to TbPTR1 and TbAK, respectively, as well as with TbUDPGE (see Table S19).
Left: Lowest-energy docked pose of 1,3,6,8-tetrahydro-2,5-dimethoxyxanthone. Right: Lowest-energy docked pose of (E)-ethyl 4-methoxycinnamate with T. brucei triosephosphate isomerase (TbTIM, PDB 1iih [50]).
Strychnos spinosa
Phytochemicals isolated from Strychnos spinosa include secoiridoids [95], indole, pyridine, and naphthyridine alkaloids [40], sterols and triterpenoids [96] (Table S20). Relatively small pyridine and naphthyridine alkaloids from Strychnos spinosa showed preferential docking to TbPTR1 and/or TbTIM. The indole alkaloids akagerine, 10-hydroxyakagerine, and kribine also docked preferentially to TbPTR1, while iridoid glucosides preferred TbUDPGE. Both sterols and triterpenoids from S. spinosa selectively docked with TbCYP51, similar to what was observed with L. inermis sterols and triterpenoids (see above), but these compounds also showed notably strong docking with TbODC. Interestingly, a comparison of docking energies of triterpenoid and steroid ligands with their antitrypanosomal activities [96] shows no correlation, even comparing TbCYP51 docking or TbODC docking. Plots of log(IC50) vs. docking energies gives R2 values of 0.043 and 0.007 for TbCYP51 and TbODC, respectively. It may be that inhibition of some other protein target [8], [9] is the biochemical mechanism of activity for these compounds.
In terms of natural products drug discovery, it is useful to examine whether different phytochemical classes show selectivity for particular protein targets. Simple flavonoid ligands showed docking preferences for TbPTR1 and TbUDPGE. Flavonoid gallates, on the other hand, were shown to be promiscuous docking ligands to all protein targets, but were particularly strongly docking with TbAK, TbPRT1, TbCYP51, and TbNH. Likewise, flavonoid glycosides tended to be promiscuous docking agents, but with preference for TbAK, TbPRT1, and TbNH. Oligomeric flavonoids (tannin-like polyphenolics) showed strong docking to TbAK. The diversity of flavonoid structures has led to diverse biological activities, including antiprotozoal activity, but the modes of antiprotozoal activity have not been well elucidated [97].
As previously noted (see above), triterpenoid ligands were largely selective for TbCYP51. Withanolide triterpenoids also showed a docking preference for TbCYP51, while limonoids preferentially docked with TbAK as well as TbCYP51. Not surprisingly, sterols showed a propensity to dock with TbCYP51, but also docked strongly with TbUDPGE.
All of the anthraquinone ligands examined in this docking study, docked with strong binding energies to TbPRT1. Likewise, xanthone ligands exhibited docking selectivity for TbPTR1. Naphthoquinones, on the other hand, docked preferentially with TbTIM. Most chromene ligands also showed notable docking energies to TbTIM. The phenylpropanoids examined showed preferences for TbTIM as well as TbUDPGE, while glycoside derivatives of phenylpropanoids showed selectivity for TbDHFR.
Berberine alkaloids docked preferentially to TbPTR1 while aporphine alkaloids showed some selectivity for TbPTR1 and TbUDPGE. Piperidine alkaloids were also selective for TbUDPGE. Pyrazole and pyridine alkaloids, on the other hand, preferred docking to TbTIM. A total of 93 indole alkaloids were examined in this docking study and many of them showed notable docking energies with TbUDPGE and some with TbAK and TbPTR1. Glycoside derivatives of alkaloids also preferentially docked with TbUDPGE.
Overall, the protein objects most targeted by the phytochemical ligands in this study were TbUDPGE, targeted by many alkaloids; TbPTR1, preferred by planar-like ligands; TbCYP51, which docked terpenoid ligands well; and TbAK, which docked many different classes of phytochemicals. Those proteins least preferred in terms of docking energies were rhodesain, TbCatB, and TbNDRT.
Rhodesain and TbCatB are both cysteine proteases with relatively small binding sites. It may be that the docking energies reflect the fact that only relatively small ligands, with inherently small docking energies, can fit well into the binding sites of these two proteins. The docking energies do not, however, reflect the potential for covalent bonding to the active sites of these proteins. It is useful, therefore, to examine small electrophilic ligands for energetically favorable docking orientations that would allow for reaction of nucleophilic amino acid side chains to the electrophilic sites of the ligands.
Although umbelliferone does not dock with particularly strong energies to rhodesain or TbCatB, it does dock in poses such that the nucleophilic Cys25 of rhodesain or Cys122 of TbCatB are poised to undergo conjugate addition to the pyrone ring (Fig. 11). The S atom of Cys25 is 3.16 Å from C(4) of docked umbelliferone in rhodesain, while in TbCatB, Cys122 is 3.65 Å from C(4) of umbelliferone. Coumarins have been shown to be trypanocidal agents [98] and it has been suggested that umbelliferone undergoes conjugate addition with available cysteine thiol groups [99].
Left: In the active sites of rhodesain (PDB 2p7u [40]). Right: In the active site of TbCatB (PDB 3hhi [46]).
Many naphthoquinones have been shown to be antitrypanosomal [100], and are suspected to interfere with redox thiol metabolism by inhibition of TbTR [101], [102]. There are docking poses, albeit not the lowest-energy poses, of isoplumbagin (docking pose energy = −9.9 kcal/mol) and lawsone (docking pose energy = −8.6 kcal/mol) with TbTR such that these quinone ligands are in the proximity of reduced trypanothione (Fig. 12). Similarly, both isoplumbagin and lawsone dock with the cysteine proteases rhodesain and TbCatB with the electrophilic carbons near the active-site cysteine residues (Fig. 13). N. laevis furanonaphthoquinones (α-lapachone derivatives) also dock with rhodesain in poses such that the nucleophilic Cys25 can undergo Michael addition to the quinone ring (Fig. 14). None of the furanonaphthoquinones docked near the trypanothione thiol groups in TbTR, however.
The docked poses are isoplumbagin (left) and lawsone (right) in the proximity of trypanothione.
The S⋅⋅⋅C(3) = 3.18 Å. Right: Lowest-energy docked pose of lawsone in the active site of T. brucei cathepsin B (TbCatB, PDB 3hhi [46]; S⋅⋅⋅C(2) = 3.73 Å).
Left: With rhodesain (PDB 2p86 [41]). Right: With TbCatB (PDB 3hhi [46]). Note the proximity and orientation of the quinone moiety with the cysteine sulfur atoms in the active sites.
This in-silico investigation suggests that trypanosomal phytochemicals may target different protein targets. There are several caveats to these docking results: (a) many of the phytochemical agents may not be bioavailable due to limited solubility, membrane permeability, hydrolysis, or other metabolic decomposition; (b) tannins and other polyphenolics are promiscuous protein binding agents and are likely, therefore, not selective antitrypanosomal ligands; (c) the docking studies do not account for synergism in bioactivity of phytochemicals; (d) this current study does not address the binding of ligand to human homologous isozymes, which may also be targeted; (e) there are likely additional phytochemicals in each of the medicinal plants that have not been isolated or identified; and (f) there are likely additional trypanosomal proteins or other biochemical targets that have not yet been identified. Nevertheless, this in-silico molecular docking study has provided evidence for what phytochemical classes and structural manifolds are targeting particular trypanosomal protein targets and could provide the framework for synthetic modification of bioactive phytochemicals, de novo synthesis of structural motifs, and further phytochemical investigations.
Supporting Information
Table S1.
Plants that have ethnopharmacological uses as antiprotozoal agents in West Africa.
Table S2.
Lowest-energy docking energies (kcal/mol) for Acacia nilotica phytochemicals with Trypanosoma brucei protein targets.
Table S3.
Lowest-energy docking energies (kcal/mol) for Ageratum conyzoides phytochemicals with Trypanosoma brucei protein targets.
Table S4.
Lowest-energy docking energies (kcal/mol) for Annona senegalensis phytochemicals with Trypanosoma brucei protein targets.
Table S5.
Lowest-energy docking energies (kcal/mol) for Bridelia ferruginea phytochemicals with Trypanosoma brucei protein targets.
Table S6.
Lowest-energy docking energies (kcal/mol) for Carapa procera phytochemicals with Trypanosoma brucei protein targets.
Table S7.
Lowest-energy docking energies (kcal/mol) for Enantia chlorantha phytochemicals with Trypanosoma brucei protein targets.
Table S8.
Lowest-energy docking energies (kcal/mol) for Garcinia kola phytochemicals with Trypanosoma brucei protein targets.
Table S9.
Lowest-energy docking energies (kcal/mol) for Khaya ivorensis and Khaya senegalensis phytochemicals with Trypanosoma brucei protein targets.
Table S10.
Lowest-energy docking energies (kcal/mol) for Lawsonia inermis phytochemicals with Trypanosoma brucei protein targets.
Table S11.
Lowest-energy docking energies (kcal/mol) for Morinda lucida phytochemicals with Trypanosoma brucei protein targets.
Table S12.
Lowest-energy docking energies (kcal/mol) for Morinda morindoides phytochemicals with Trypanosoma brucei protein targets.
Table S13.
Lowest-energy docking energies (kcal/mol) for Nauclea latifolia phytochemicals with Trypanosoma brucei protein targets.
Table S14.
Lowest-energy docking energies (kcal/mol) for Newbouldia laevis phytochemicals with Trypanosoma brucei protein targets.
Table S15.
Lowest-energy docking energies (kcal/mol) for Physalis angulata phytochemicals with Trypanosoma brucei protein targets.
Table S16.
Lowest-energy docking energies (kcal/mol) for Picralima nitida phytochemicals with Trypanosoma brucei protein targets.
Table S17.
Lowest-energy docking energies (kcal/mol) for Prosopis africana phytochemicals with Trypanosoma brucei protein targets.
Table S18.
Lowest-energy docking energies (kcal/mol) for Rauwolfia vomitoria phytochemicals with Trypanosoma brucei protein targets.
Table S19.
Lowest-energy docking energies (kcal/mol) for Securidaca longipedunculata phytochemicals with Trypanosoma brucei protein targets.
Table S20.
Lowest-energy docking energies (kcal/mol) for Strychnos spinosa phytochemicals with Trypanosoma brucei protein targets.
Author Contributions
Conceived and designed the experiments: WNS IVO. Performed the experiments: WNS IVO. Analyzed the data: WNS IVO. Contributed reagents/materials/analysis tools: WNS. Wrote the paper: WNS IVO.
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- 90. Ratle G, Monseur X, Das BC, Yassi J, Khuong-Huu Q, et al. (1966) [Prosopine and prosopinine alkaloids of Prosopis africana (Guill and Perr) Taub. (preliminary note)]. Bul Soc Chim Fr 9: 2945–2947.
- 91. Sabri NN, Court WE (1978) Stem alkaloids of Rauwolfia vomitoria. Phytochemistry 17: 2023–2026.
- 92. Amer MM, Court WE (1980) Leaf alkaloids of Rauwolfia vomitoria. Phytochemistry 19: 1833–1836.
- 93. Marion Meyer JJ, Rakuambo NC, Hussein AA (2008) Novel xanthones from Securidaca longipedunculata with activity against erectile dysfunction. J Ethnopharmacol 119: 599–603.
- 94. Scandola M, Games DE, Costa C, Allegri G, Bertazzo A, et al. (1994) Structural study of alkaloids from Securidaca longipedunculata roots. II. Isolation and characterization by supercritical fluid chromatography/mass spectrometry. J Heterocycl Chem 31: 219–224.
- 95. Itoh A, Oya N, Kawaguchi E, Nishio S, Tanaka Y, et al. (2005) Secoiridoid glucosides from Strychnos spinosa. J Nat Prod 68: 1434–1436.
- 96. Hoet S, Pieters L, Muccioli GG, Habib-Jiwan JL, Opperdoes FR, et al. (2007) Antitrypanosomal activity of triterpenoids and sterols from the leaves of Strychnos spinosa and related compounds. J Nat Prod 70: 1360–1363.
- 97. Kerboeuf D, Riou M, Guégnard F (2008) Flavonoids and related compounds in parasitic disease control. Min Rev Med Chem 8: 116–128.
- 98. Pizzolatti MG, Mendes BG, Cunha A, Soldi C, Koga AH, et al. (2008) Trypanocidal activity of coumarins and styryl-2-pyrones from Polygala sabulosa A.W. Bennet (Polygalaceae). Rev Bras Farmacog 18: 177–182.
- 99. Rodgriquez AM, Enriz RD, Santagata LN, Jáuregui EA, Pestchanker MJ, et al. (1997) Structure-cytoprotective activity relationship of simple molecules containing an α,β-unsaturated carbonyl system. J Med Chem 40: 1827–1834.
- 100. Salas CO, Faundez M, Morello A, Diego Maya J, Tapia RA (2011) Natural and synthetic naphthoquinones active against Trypanosoma cruzi: An initial step towards new drugs for Chagas disease. Curr Med Chem 18: 144–161.
- 101. Salmon-Chemin L, Buisine E, Yardley V, Kohler S, Debreu MA, et al. (2001) 2- and 3-Substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: Synthesis and correlation between redox cycling activities and in vitro cytotoxicity. J Med Chem 44: 548–565.
- 102. De Molfetta FA, de Freitas RF, da Silva ABF, Montanari CA (2009) Docking and molecular dynamics simulation of quinone compounds with trypanocidal activity. J Mol Model 15: 1175–1184.


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Main Page
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Main Nibbles
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From A To Z
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KAREN HOCHMAN is Editorial Director of THE NIBBLE.
July 2007
Updated March 2009
This is Page 3 of a four-page article. Discover Caramel Apple, Chocolate, Coffee Toffee, Licorice, Pecan Vanilla and Vanilla Nut caramels. Click on the black links below to visit other pages.
Since 1938, Gifford's has been pleasing the D.C. crowd with ice cream and candy. The caramels are much softer chews and a real find for people who have steered clear of caramels for fear of fillings, braces and such. In Caramel Apple, Chocolate, Coffee Toffee, Vanilla and Vanilla Nut (with pecan pieces), the Vanilla and Chocolate are available in the summer; the other flavors return in the fall. Coffee Toffee has the best coffee flavor of the coffee caramels we tried.
Perhaps the most classic of the caramels, these cream caramels from Utah have all the old-fashioned flavor and chewiness one could ask for. All four flavors we had were outstanding—Vanilla Cream, Licorice, Mocha (very chocolaty) and Pecan (Vanilla Cream with chopped pecans). The Vanilla Cream are perhaps our favorite vanilla caramels; and the Licorice must not be overlooked. The company also makes yummy pretzel rods, dipped in caramel and coated with white chocolate.
*Prices and product availability are verified at publication but are subject to change. Shipping is additional. These items are offered by a third party and THE NIBBLE has no relationship with them. Purchase information is provided as a reader convenience.
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subset: commoncrawl


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Persistence, perseverance—and sometimes plain pestering: these are some of the strategies that helped Mallika Dutt and Jane Golden become successful activists for their respective public-interest passions. Their far-ranging and sometimes feisty discussion about "Women Leading the Way" was part of the festivities celebrating the official ribbon-cutting and opening of The Diana Center on February 3. The panel was organized by The Athena Center for Leadership Studies. As Kathryn Kolbert, the center's director and the panel's moderator notes, one of the goals of The Athena Center is to "showcase inspiring women leaders who have used their energies to make the world a better place. Both women have been incredibly creative in their work."
Dutt is founder and United States director of Breakthrough, an international human-rights organization that addresses issues like violence against women, sexuality and HIV/AIDS, immigrant rights, and racial justice through popular culture, media, community education, and leadership development. The organization runs programs in India and America. Golden is director of the City of Philadelphia's Mural Arts Program, which has designed and installed more than 3,000 murals throughout the city, transforming local communities and inspiring residents.
"The underlying philosophy is to articulate women's rights as human rights," explains Dutt, a longtime human-rights activist who once worked for the Ford Foundation. She showed several award-winning Bollywood-style videos that were designed to deal with the problems of violence against women and the stigma of HIV/ AIDS, as part of public service campaigns in India. "Usually we talk about how culture and religion constrain and restrain women's rights," says Dutt. "This all began as an experiment to take cultural experiences and create a human-rights culture. The way that media shapes your life will be absolutely critical to create human-rights solutions."
Golden, who grew up in a "mural-friendly household where my parents always talked about the art created during the WPA," was an artist who channeled her impulse for social change into public art projects. She first worked on public murals with teenagers on probation in Santa Monica, California. When Golden moved back East, she started working with teenagers from inner-city Philadelphia as part of an anti-graffiti campaign.
"I could put kids to work," says Golden. "There weren't opportunities for [those] who had talent, and interest, in art. What I love about murals is that you have many, many stakeholders; you engage with the community. Murals become a tipping point, turning around communities.... That was my epiphany."
For both Dutt and Golden, these leadership lessons could be applied anywhere. "Leadership is about you, wherever you are," insists Dutt. "It's how you treat everybody. It's not about violators/victims. Human rights is about where you start as an individual. Leadership is whatever you can do in the space you occupy to bring human rights home."
For Golden, it's about "tenacity and perseverance, hope and faith, the determination one has to cultivate.... It's the kind of courage that has to be summoned, with the patience to understand that it may not be everything you want. Leading is about moving forward no matter what."
-by Merri Rosenberg '78


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GIS Data Sources
Data Sources for New York State
Cornell University's Geospatial Information Repository
"CUGIR is an active online repository providing geospatial data and metadata for New York State, with special emphasis on those natural features relevant to agriculture, ecology, natural resources, and human-environment interactions."
New York State GIS Clearinghouse
The Clearinghouse provides a repository for data and metadata resources and an extensive collection of downloadable data.
Datasets of the NYS Museum
A good source for statewide bedrock and surficial geology data in New York. There are also links to historical USGS maps for New England.
NYS Geography and Mapping, NYS Data Center
The New York State Data Center's Geography and Mapping site provides interactive query access to geographic boundary files, Census attribute data for various levels of statistical and political geography, and predefined thematic maps illustrating various economic and demographic characteristics of the population.
Data Sources for the US and World
Geospatial One-Stop
The one stop shop for Federal, State and Local GIS data provided by the Federal Government.
The National Map Viewer
"The National Map is a consistent framework for geographic knowledge needed by the Nation. It provides public access to high-quality, geospatial data and information from multiple partners to help support decision making by resource managers and the public." The geographic information available from The National Map includes orthoimagery (aerial photographs), elevation, geographic names, hydrography, boundaries, transportation, structures, and land cover.
US Topo
The next generation of digital topographic maps from the USGS. Arranged in the traditional 7.5-minute quadrangle format, digital US Topo maps are designed to look and feel like the traditional paper topographic maps. Users can turn geographic data layers on and off; zoom in and out to highlight specific features or see a broader context; and print the maps, in their entirety or in customized sections, on a wide variety of printing devices.
UN Environmental GeoData Portal
A source for data sets used by UNEP and its partners in the Global Environment Outlook (GEO) report. The online database contains national, subregional, regional and global statistics and geospatial data sets (maps), covering themes like Freshwater, Population, Forests, Emissions, Climate, Disasters, Health and GDP. Display them on-the-fly as maps, graphs, data tables or download the data in different formats."
Maps Ready to Print
Perry-Castañeda Library Map Collection
The University of Texas' extensive collection of printable maps - both modern and historical.
United Nations Cartographic Section
More than 100 General Maps are currently available. Includes general maps, peacekeeping maps and various thematic maps. Most are in PDF format.
David Rumsey Map Collection
The David Rumsey Historical Map Collection has over 10,000 maps online. The collection focuses on rare 18th and 19th century North and South America maps and other cartographic materials.
A to Z Maps
This is also the worlds largest subscription-based database of proprietary, royalty-free world, continent, country, and state maps. Included in the 145,000+ maps are: political maps, physical maps, outline maps, population maps, precipitation maps, climate maps, and other thematic maps. GIS data for states, countries, and global levels are also available in shapefile, e00, and mdb formats.
Interactive Maps
St. Lawrence University Map Server
The SLU Map Server contains interactive maps created by the GIS program using ArcIMS. Contact Carol or Louise to find out how to create a mapservice for your course.
St. Lawrence County OpenGeo Portal
The SLC OpenGeoPortal is an interactive web viewer for the county using basemap layers from Google, Bing, Yahoo, OSM, ESRI, USGS, NYSDOP and local layers including Tax Parcels, Soils, Wetlands, School Districts, Voting Districts & more. Data are available for download as WMS, WFS, ESRI shape files, KML and KMZ files. Uploads of KML files allow users to create their own mashups.
National Geographic's Maps and Geography WWW Site
Interactive maps of anywhere on the planet.
ArcGIS Online
An online way to create maps. Access free high quality ready-to-use base maps, apps, and tools published by Esri and other GIS users, and share your own content with a broad community of users. Map services can be used with ArcGIS 9.3.1 and higher
Virtual Globes
NASA's Worldwind
Freely downloadable from NASA's website, Worldwind offers 3D global coverage of current satellite imagery and many other layers.
Google Earth
Freely downloadable from Google, this software also provides global coverage of satellite and aerial imagery with 3D views.
GIS Software Resources
Environmental Systems Research Institute - ESRI
The world leader in GIS development. Their support page is a great resource if you are having problems with ESRI software.
Erdas Imagine Support - Leica Geosystems
For support with Erdas Imagine 8.7 click on the support tab.
The Virtual Campus provides live training seminars, free online workshops and many other training options. Contact the GIS staff if you would like to obtain a course access code.


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Indians invite five from player development system
CLEVELAND, OH - The Cleveland Indians today announced the club has extended non-roster invitations to Major League spring training camp to the following players: 1B JESUS AGUILAR, RHP PRESTON GUILMET, RHP MATT LANGWELL, CA ROBERTO PEREZ and LHP GIOVANNI SOTO.
CLEVELAND, OH - The Cleveland Indians today announced the club has extended non-roster invitations to Major League spring training camp to the following players: 1B JESUS AGUILAR, RHP PRESTON GUILMET, RHP MATT LANGWELL, CA ROBERTO PEREZ and LHP GIOVANNI SOTO.
1B JESUS AGUILAR born 6/3/1990, age 22 b-R/t-R/6-3/190
Enters the season rated the 10th-best prospect in organization according to Baseball America. In 127 games between A Carolina and AA Akron last season, he hit a combined .280 (123-440) with 31 doubles, 2 triples, 15 HR and 71 RBI, which ranked 4th among Indians farmhands. The 6-3, 257 lb., first baseman played for the World Team in the 2012 All-Star Futures Game in KC. In 2011, Aguilar ranked among the organizational leaders in RBI (82, 1st), home runs (23, 2nd) and hits (131, 3rd) and was named a Midwest League Postseason All-Star and an MiLB.com Organization All-Star. The native of Venezuela signed as a non-drafted free agent on Nov. 13, 2007.
RHP PRESONT GUILMET born 7/27/1987, age 25 b-R/t-R/6-1/190
Spent the entire 2012 season at Class AA Akron where he led the organization with 24 saves in 29 chances. The Roseville, CA native was named to the Eastern League Postseason All-Star team after tying for the league lead in saves and leading the circuit in games finished (39), while holding opponents to a .211 average against (41-194). In 2011, Guilmet (GILL-met) finished T1st among Indians farmhands with 35 saves in 36 chances and earned Carolina League Mid- and Postseason All-Star honors. The 6-2, 200 lb. right-hander was originally selected by the Tribe in the ninth round of the June 2009 Draft out of Arizona.
RHP MATT LANGWELL born 5/6/1986, age 26 b-R/t-R/6-0/220
Split the 2012 season between Class AA Akron and Class AAA Columbus compiling a 4-0 record with a 2.74 ERA in 42 relief outings (69.0IP, 59H, 21ER, 27BB, 81K, .231AVG, 0HR). The 6-2, 220 lb. righty averaged 10.6 strikeouts per 9.0IP for the season and had a BB/SO ratio of 3.00, while holding right-handed hitters to a .211 average (30-142). A resident of College Station, TX, Langwell was selected by the Indians in the 11th round of the June 2008 First-Year Player Draft out of Rice.
CA ROBERTO PEREZ born 12/23/1988, age 24 b-R/t-R/5-11/225
Played at Class AA Akron in 2012 where he batted .212 (60-283) with 16 doubles, 2 triples, 1 HR and 31 RBI in 95 games and threw out 41% (35-of-86) of the baserunners attempting to steal off him. In 2011, Perez played in the Arizona Fall League and was named a Midwest League All-Star in 2010. The Mayaguez, PR native owns a minor league career OBP of .364. He was selected by the Indians in the 33rd round of the June 2008 First-Year Player Draft out of Lake City Community College in Lake City, FL.
LHP GIOVANNI SOTO born 5/18/1991, age 21 b-L/t-L/6-2/190
Pitched for Class AA Akron in 2012 posting a 6-9 record with a 3.93 ERA in 22 starts (121.1IP, 111H, 53ER, 49BB, 100K, .247AVG). He ranked T2nd in the Eastern League with 2 complete games, including a 9.0IP no-hitter on July 15 vs. Altoona, the 2nd in Aeros franchise history (0H, 1R/0ER, 3BB, 6K, 104P). The 6-2, 190 lb., lefty will pitch for Puerto Rico in the 2013 World Baseball Classic. Soto was acquired Tigers by the Indians from the Detroit in exchange for INF Jhonny Peralta on July 29, 2010.


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Ceramic Tool Kit
by Kemper
The seven most practical and popular Kemper tools for ceramists. The complete tool kit contains one each: wire loop sgraffito, cleanup tool, cut out tool, palette knife, lace tool, sabre saw, salt & pepper drill.
Ask a question about Ceramic Tool Kit Ask a question about this product
Average User Rating: Based on (3 Reviews)
5 3
John Arthur from Spokane WA says:
Well made,mostly in stainless steel, well fitted into the well made holders. Kemper is always a class act. Haven't the least idea what some of these tools will do, but that is why I got them.
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text:
In mid-2011, a study was conducted by IFS North America and Mint Jutras, among manufacturing executives and professionals of middle market to large manufacturers, to understand how usability challenges may cause individuals to work outside established enterprise software systems, generating lost value for the manufacturer. Working outside of enterprise systems results in barriers to the enterprise-wide visibility that ERP and other enterprise software are designed to provide, enterprise risk as work is performed outside of the security and traceability provisions of enterprise software, and places enterprise data in online repositories where data ownership and security are even more questionable.
The study focused on the degree to which corporate citizens will take action as the result of enterprise software usability challenges including the use of various types of PC-based software and the types of online free or low-cost applications. Generational differences were also explored using four different age groups.
Ten Tips for Getting the Most from Your Mentor Both parties need to take an active role for this relationship to pay off.
Salary Negotiations: Insider Secrets Recruiter reveals insider's secrets to getting paid what you want.
Top 25 Companies for Work-life Balance See which companies employees rank highest for work-life balance.
Related Topics : A Big Market for Big Data Jobs, Midmarket CIO, IT Management Automation, SharePoint, Technology Markets
The gig economy is clearly disrupting the tech industry, both in positive and negative ways. ... More >>
Is fake news a security issue? Some say yes, as it can be used as a social engineering tool to spread disinformation and conceivably to get unsuspecting users to click on malicious links. ... More >>
Executives at several top tech firms outline the skills they need now and in the near future, including IaaS and IoT security expertise. Other skills listed may surprise you. ... More >>


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A recent survey by Mashable found that 84% of companies running social media programs don't measure return on investment (ROI). A lot of brands both big and small are starting to leverage social media, but how do you measure the impact that social media is having either on sales or in brand lift? Assessing social media ROI is fairly hard due to the nature of the medium but it is not impossible.
Key Performance Indicators
At the launch of any social media campaign, you need to define some key performance indicators which are your measures of success. If you are putting in X dollars into a social media campaign what do you want to achieve? i.e. If you are going to setup a Facebook fan page for your service or product and then purchase some Facebook ads to drive to it, how many fans do you expect to get in return? Is 5$ per fan a reasonable amount for your brand or is it simply to expensive?
Some KPIs anyone running a social media program should monitor are as follows:
- Which social media tactics are reaching the most people and in turn producing the most traffic (twitter, blog, forum, etc)?
- Which tactics are driving the most engaged visitors (most time on site, most page views etc.) and the most high value tasks on site?
- Are your efforts attracting the right people? (measure with surveys, monitor user engagement on site).
- Based on you social media efforts, are you seeing any brand lift, positive comments in the blogosphere or increased intent to buy?
- Use a social media monitoring tool like Radian6 to monitor increases in mentions of your brand
- Use a back link checker to see if the number of hyperlinks to your site / blog / twitter etc. are increasing with time. Social media can lead to more incoming links helping you increase your organic search ranking.
- Take a look at branded search volumes that are driving to your site by looking up data in your analytics tool
If your company has not traditionally been part of the online conversation, what are you aiming for? Set some high level goals in terms of how many customer problems you want to address on forums and on Twitter on a weekly basis. If you have a dedicated Social PR resource set expectations ahead of time. You need concrete goals and then you need to work towards them. Take a look at how customers are responding to your Social Media PR efforts. Is there positive feedback when you help a customer using Twitter when other channels such as a call center support failed to address the customers issue?
The Bottom Line
In short, measurement is all about the numbers. If there is any way to assign a number to some facet of your social media campaign you need to know that number, take a measurement as a baseline and work to improve it. You also need to set goals ahead of time and works towards them. Don't spend money on a campaign or social PR effort without having defined your success metric and defined some type of budget per high value task.


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In "Verification of Truth of the Statement" questions, it is required to stress only on truth of facts that always hold. Questions are asked in context of a particular thing or factor that is always characterized by a specific part. The alternatives other than correct answer also seem to bear a strong relationship with thing mentioned. So, absolute truth is to be followed.
Choose the best alternative as the answer.
An oasis always has
A. Travellers
B. Water
C. Sand
D. Camels
E. Forests
Answer: B . WaterTweet


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Staff writer
The countdown to the 92nd annual July Fourth Celebration grows more apparent as the day draws nearer.
Bunting and holiday decorations are beginning to appear on homes and businesses. The "Pyro Crew" is spending quality time at the city park on Tuesday and Thursday evenings working on the ground displays. Admission buttons will be on sale by the end of the week.
Fourth Celebration Society co-chairman Lisa Hodges said the committee has been contacted by a group of classic car enthusiasts who will bring their vehicles to the city park for a "Show and Shine" from 11 a.m. to 4 p.m. July 4.
"Apparently a 'Show and Shine' is a fairly low-key event," Hodges said. "There is no entry fee and there are no prizes. The group is planning to spend the day in the park with their friends and families, showing off their vehicles and visiting with people who enjoy classic cars. Some of them plan to be in the parade, and we are glad to have them come to Peabody for the day."
The Fourth Celebration Society admits that numbers play a huge part in promoting the event.
"We are always glad to share information with those who plan to attend," Hodges said. "Once again, those watching the fireworks show will see more than 1 million fireworks fired between the beginning mortars and the Battle of New Orleans finale. This will be the third consecutive year for exploding that many. It makes for a great show."
Admission to the 92nd annual fireworks show costs $3. The admission button also gets patrons into all the events at the park, no matter what time they arrive.
"We usually don't have people at the gates until later in the day," she said. "Admission to the park is free during the day, but buttons are required to attend the fireworks show.
"My mom is the button queen. She has made 3,200 admission buttons since the first part of May. She likes it when we sell out and don't have any left over."
Early on the Fourth, the park will be the site of a horseshoe tournament and flea market. Both will start at 8 a.m. Food vendors will be set up during the day, and there will be free swimming at the Peabody pool and kid's games in the park during the afternoon.
Other events will include the sixth annual Bob Phillips, Jr. Memorial Texas Hold 'Em Poker Tournament at 7 p.m. June 29 at the Peabody American Legion in downtown Peabody. The Legion also will be the site of an alumni dance beginning at 9 p.m. on July 3. Proceeds from both events fund scholarships for Peabody-Burns High School graduates.
A perennial favorite is the American Legion Auxiliary dog show in Santa Fe Park. The event will begin at 11 a. m. and will be open to canines from near and far. There is a $2 entry fee. Doggy prizes will be awarded to the winners.
For the first time in about 25 years, the celebration will include a volleyball tournament just east of the city park. For several years in the late 1980s, mud volleyball tournaments were held on the same space, but nothing similar has taken place since then.
The tournament this year is limited to co-ed teams with members 18 or older. The tournament will begin at 8 a.m. and end close to noon to avoid the heat of the day. Patti Traxson is in charge of rounding up teams for the event. A $20 entry fee will be required of each team. T-shirts will be given to the winning team.
For more information, visit the celebration website at http://peabodyfourth.com.


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Wheely Wanka is name of a tyre that I one day found in a ditch. This magnificant king of the highway can be rolled down a hill, at high speeds or off a cliff. The Wheely Wanka is a creature of little balance and gets filled with sand easily. It's sister creature is the tyre which can be found on the wheel of a car. The tyre can serve for the same purposes as well as going round and round, round and round all day long.
"Far out look at Wheely Wanka go"
"Far out? christ you're gay Jack"
"Far out? christ you're gay Jack"
by roasty toasty February 13, 2005


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We're #66!Posted by rtmsf on April 4th, 2008
From the in-case-you-missed-it file, and we know you did, THE Ohio State University played in the Dave Odom Invitational NIT Championship last night against UMass, and since the Buckeyes were not playing Florida in a collegiate postseason event, they actually managed to win this one 92-85.
Photo Credit: 11 Warriors
Kosta Koufos led the way for OSU with 23 pts while Ricky Harris poured in 27 for the losing team. This is probably a good thing for Thad Matta's team, as he stands to lose his top three scorers (Othello Hunter and Jamar Butler to graduation; Kosta Koufos to Europe?), leaving the Buckeyes to rely predominantly on David Lighty, Evan Turner, Jon Diebler and superfrosh BJ Mullens next season. We're not saying that a Thad Matta team is ever out of the picture, but this time next season an NIT championship may seem like manna from the gods.
Meanwhile, here was C-bus's reaction to the ever-elusive NIT title…


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Not to be lost in the discussion of the Ravens' recent free-agent losses: they went through the same thing last offseason.
In 2012, the Ravens lost offensive guard Ben Grubbs, outside linebacker Jarret Johnson and four other contributors in free agency. On the other side of the ledger, Baltimore added safety Sean Considine and cornerback Corey Graham — players best known, to that point, for their special-teams work.
Well, Graham ended up being much more than a coverage ace. His play on defense was a revelation, a boost to the secondary after corner Lardarius Webb left the lineup. And while the Ravens could have used some of the players they had lost in the offseason . . . well, Baltimore managed pretty well in the end.
Moreover, the Ravens will get some 2013 draft picks for their troubles. The NFL announced Monday that Baltimore will receiver four compensatory selections in April's draft. Only the Falcons, who lost four free agents and signed none, will get as many compensatory selections.
Per NFL rules, a maximum of four compensatory picks can be awarded to a team for their net free-agent losses in a given offseason. Compensatory picks are distributing using a metric tied to playing time, salary and postseason awards garnered by the departed free agents. Compensatory selections cannot be traded.
The highest compensatory selection will go to Houston (Round Three, No. 95 overall), which lost Mario Williams to Buffalo last March. The Chiefs (No. 96) and Titans (No. 97) also received third-round selections.
Here's the complete rundown of 2013 compensatory picks:
Atlanta Falcons (four picks): one fourth-rounder (No. 133), three seventh-rounders (Nos. 243, 244, 249).
Baltimore Ravens (four): one fourth-rounder (No. 130), one-fifth-rounder (No. 168), one sixth-rounder (No. 203), one seventh-rounder (No. 247).
Tennessee Titans (three): one third-rounder (No. 97), one sixth-rounder (No. 202), one seventh-rounder (N0. 248).
San Francisco 49ers (three): one fourth-rounder (No. 131), two seventh-rounders (Nos. 246, 252).
Houston Texans (two): one third-rounder (No. 95), one sixth-rounder (No. 201).
Kansas City Chiefs (two): one third-rounder (No. 96), one sixth-rounder (No. 2o4).
Detroit Lions (two): one fourth-rounder (No. 132), one seventh-rounder (No. 245).
Miami Dolphins (two): one fifth-rounder (No. 166), one seventh-rounder (No. 250).
Cincinnati Bengals (two): two seventh-rounders (Nos. 240, 251).
Seattle Seahawks (two): two seventh-rounders (Nos. 241, 242).
Green Bay Packers (one): a fifth-rounder (No. 167).
Oakland Raiders (one): a sixth-rounder (No. 205).
Pittsburgh Steelers (one): a sixth-rounder (No. 206).
Philadelphia Eagles (one): a seventh-rounder (No. 239).
New York Giants (one): a seventh-rounder (No. 253).
Indianapolis Colts (one): a seventh-rounder (No. 254).


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For the second time in two years, the European Champions League final four has consisted of three English teams, thus creating one all-English semi-final (Manchester United vs. Arsenal; Chelsea is the other English semi-finalist). But the UEFA Cup, Europe's secondary club competition, has gone one better: it features one an all-German semi (Werder Bremen vs. Hamburg) and one all-Ukrainian affair.
The latter is the more interesting in part because of political considerations. It pits Dynamo Kiev against Shakhtar Donetsk. Dynamo Kiev are the New York Yankees of that part of the world. They were the best club side in the old Soviet Union and, as expected, continued to be the top club in Ukraine throughout the 1990s.
Recently, however, Shakhtar Donetsk has given them more than a run for their money. The club is bankrolled by Ukrainian billionaire businessman and football fanatic Rinat Akhmetov, an oligarch with resources to rival those found anywhere in Russia, England, Spain, or Italy (at one point Korespondent magazine rated him the richest man in Europe). As such he has been able to sign stars like Elano (a starter for the Brazilian national team who has since moved on the Manchester City), Ilsinho, who has also played for Brazil, Mexican sensation Neri Castillo, and Cristiano Lucarelli, a former top scorer in Italy's Serie A, who is now back in Italy.
Riding Akhmetov's backing, Shakhtar Donetsk in this decade has won four of eight Ukrainian league titles as well as four of eight domestic cup crowns.
The rivalry between the Kiev and Donetsk sides would be huge even if it implicated only sports. But there are political considerations too. Akhmetov supported Viktor Yanukovych, then Prime Minister of Ukraine, in the 2004 elections. He thus stood in opposition to the Orange Revolution, a phenomenon associated with Kiev, which is far more cosmopolitan than Donetsk. Donetsk also tends to be pro-Russian. Many of the falsified votes for Yanukovych are said to have come from Donetsk and the surrounding region.
Much has changed in Ukraine since 2004, both politically and economically. But the rivalry between Dynamo Kiev and Shakhtar Donetsk remains as intense as ever. So too, I suspect, do the political undercurrents of that rivalry.
UPDATE: Shakhtar Donetsk got a 1-1 draw in the first leg at Kiev. The second leg will be played in Donetsk. An away draw with a goal is a good result (away goals are the tie-breaker).
In honor of the occasion, I've taken the liberty of posting the Shakhtar Donetsk which is surely being sung over rounds of vodka throughout the east Ukrainian steppe as I write:
Glory to you, Shakhtar!
Heavens of football stars
Will always be on your side,
And the light of your best dreams
is shining from above.
Beauty of green fields, that's for you, Shakhtar.
My fate is in your hands, you are the best, Shakhtar.
And for you, Shakhtar, the medal of my love
Will always shine on pitch where you are,
And forever will protect you from defeat
The brightest football star!


text:
Peter from Double Helix Cables tore apart his new Lightning connector as soon as it arrived, to investigate what's inside and why Apple charges £25 for the product.
Peter claims that the adapter is "beautifully manufactured," and "isn't going to be modded by anyone anytime soon."
"To access the contacts for the audio output to somehow hack a cable to this and make a dock audio output cable would require a Ph.D. in electrical engineering and specialized tools," he says.
The adapter contains several chips in order to allow Lightning devices to work with 30-pin connector accessories.
"The chips look unfamiliar, but with the same metal finish and some have lasered text," Peter says. "They all appear to be custom and trying to figure out what does what is fruitless. I really took this apart for the DIY community to ascertain if the DAC [digital-to-analog converter] in this thin is actually good, but it's quite unclear."
"Nobody would balk at paying $29 for this after they see what's inside, though," he added.
We received our Lighting to 30-pin adaptor and Lighting to USB cable yesterday, and you can check out our unboxing here.
One Chinese company claims to have successfully cloned Apple's Lightning cable, and has produced its own third-party cable this week. Plus, it glows!
See also:
Steve Wozniak calls Apple arrogant: 'I wish the iPhone 5 was wider'


text:
Rick bribes the staff into leaving him alone
They return to work.
or at least, until the Sanorumites shove them away from their consoles.
The Cult of Paul-Tymon555
"Behind you!"
"Nevermind" another bad skill role for the cultists
Cultists move in.
"let me go?"
The Rent is 2 Damn High Party-silverdream
Jimmy urges his followers forwards.
two cultists are flattened, and a Romney supporter manages to bail. Will Jimmy's attack hit?
apparently not.
The last criminal realizes that it's probably safer to wait in the car.
Winning our Future-Mgb519
mgb519 wrote:Newt Gingrich should become the McCormick Mechanical Reaper, capable of doing the work of 100 men.
The last tea Partier picks himself up.
Here comes the stampede!
One Romney supporter is trampled and the other pinned to the door. but where's jimmy?
here he is.
Americans for a Better Tomorrow, Tomorrow-Falk
" Free bananas!"
Blah blah blah
"Fly you fools! it will be the death of us all!"
"Attention staff--Kill everyone!"
Newt is pinned to the controls, one santorumite is killed by a...dollar? Rick is attacked, but gets a redshirt.
Things are not looking good for the Red, White, And Blue Fund.
Or for Newt.


text:
Thom's Subtle & Simple Bedroom
Like this entry? Favorite it below!
- Name:
- Thom
- Location:
- Boston, MA
- Division:
- United States
- What do you love about your bedroom?:
- The color and light.
- What are your tips for creating a beautiful, healthy and organized bedroom?:
- Remove clutter. Subtle color. Rich fabrics.
- In modern homes, bedrooms have become more than just a place to sleep; they can be a retreat, a home office, a library, a relaxation zone. What are some ways you make the most of your bedroom?:
- This is not a modern home. No electronics. Nothing to distract from a peaceful restful environment.


text:
|Die Seltsamen at a bookstore in Zürich. Thank you, Orell Füssli!
But OH WELL. I want to use this post to say a huge thank you to a bunch of people.
Thank you to my German publisher Diogenes for picking up the book, and for having an awesome team of people who are doing a ton to get the word out about it, and for giving the book it's striking cover that pops so nicely from all the other editions of TP. I love that cover.
|Where's Waldo.
And the biggest thank you's to the awesome Swiss and German-language readers who have been picking it up and blogging and tweeting about it. Danke euch viel mals. :)