Nucleoside dimers analogs containing floxuridine and thymidine with unnatural linker groups: synthesis and cancer line studies. Part III

Abstract

Two series of novel fluorinated nucleosides dimers with an unnatural 1,2,3-triazole linkage were synthesized. The obtained molecules were prepared using “click” chemistry approach based on copper(I) catalyzed Huisgen azide–alkyne cycloaddition. It was performed between 3′- and 5′-azido-nucleosides as the azide components, and the 3′-O- and 5′-O-propargyl-nucleosides as the alkyne components. Based on analysis of the ³ Brunton, L. L.; Lazo, J. S.; Parker, K. L. (Eds.), Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, Medical Publishing Division: New York, NY, 2006. [Google Scholar]J_HH, ³ Brunton, L. L.; Lazo, J. S.; Parker, K. L. (Eds.), Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, Medical Publishing Division: New York, NY, 2006. [Google Scholar]J_H1′C2 and ³ Brunton, L. L.; Lazo, J. S.; Parker, K. L. (Eds.), Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, Medical Publishing Division: New York, NY, 2006. [Google Scholar]J_H1′C6 we estimated conformational preferences of sugar part and orientation around glycosidic bond. All described nucleosides dimers analogs were characterized by spectroscopic methods and evaluated for their in vitro cytotoxicity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7).     

Buried Tracks: Ichnological Applications of High-Frequency Georadar

Recognition and sampling of traces in unconsolidated sands present a major challenge for ichnologists. This can be partially remedied through the application of high-resolution geophysical techniques, such as ground-penetrating radar (GPR or georadar), which uses electromagnetic impulse for continuous imaging of shallow subsurface. It addition to geological applications, GPR imaging has been used in several studies focused on animal traces as related to conservation of endangered fossorial species (Kinlaw et al., 2007 Kinlaw, A. E., Conyers, L. B. and Zajac, W. 2007. Use of ground penetrating radar to image burrows of the gopher tortoise (Gopherus polyphemus). Herpetological Review, 38: 50–56.  [Google Scholar]; Martin et al., 2011 Martin, A. J., Skaggs, S. A., Vance, R. K. and Greco, V. 2011. Ground-penetrating radar investigation of gopher-tortoise burrows: Refining the characterization of modern vertebrate burrows and associated commensal traces. Geological Society of America Abstracts with Programs, 43: 381 [Google Scholar]), slope and levee stability (Nichol et al., 2003 Nichol, D., Lenham, J. W. and Reynolds, J. M. 2003. Application of ground-penetrating radar to investigate the effects of badger setts on slope stability at St. Asaph Bypass, North Wales. Quarterly Journal of Engineering Geology and Hydrogeology, 36: 143–153.  [Google Scholar]; Di Prinzio et al., 2010 Di Prinzio, M, Bittelli, M., Castellarin, A. and Pisa, P. R. 2010. Application of GPR to the monitoring of river embankments. Journal of Applied Geophysics, 7: 53–61.  [Google Scholar]), and mapping of fossil tracks (Matthews et al., 2006 Matthews, N. A., Noble, T. A. and Breithaupt, B. H. 2006. “The application of photogrammetry, remote sensing and geographic information systems (GIS) to fossil resource management”. In Fossils from Federal Lands, Edited by: Lucas, S. G., Spielmann, J. A., Hester, P. M., Kenworthy, J. P. and Santucci, V. L. Vol. 34, 119–131. New Mexico Museum of Natural History and Science Bulletin.  [Google Scholar]; Aucoin and Hasbargen, 2010 Aucoin, C. D. and Hasbargen, L. 2010. Using GPR, GPS and close-range photography to map and characterize dinosaur tracks in the Connecticut River valley. Geological Society of America Abstracts with Programs, 42: 276 [Google Scholar]) and tracking surfaces (Webb, 2007 Webb, S. 2007. Further research of the Willandra Lakes fossil footprint site, southeastern Australia. Journal of Human Evolution, 52: 711–715. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]). Few efforts have been dedicated specifically to characterizing burrow and track characteristics (Stott, 1996 Stott, P. 1996. Ground-penetrating radar: a technique for investigating the burrow structure of fossorial vertebrates. Wildlife Research, 22: 519–530.  [Google Scholar]; Sensors & Software Inc., 2010 [compilation on geophysical projects related to animal burrows]; Buynevich and Hasiotis, 2011; Buynevich et al., 2011; Martin et al., 2011) and most of the above studies are published in journals not routinely accessed by ichnologists.     

Early Oligocene Mammal Tracks from Southeastern France

Two new sites with mammalian footprints in the early Oligocene of southeastern France are described here. They represent one of the best preserved and more numerous record of tracks and trackways in the world with more than 320 ichnites. Many of those are arranged in trackways and sometimes show pes-manus impressions, a quite rare feature in mammalian ichnology. The ichnotaxonomic study indicates the presence of perissodactyls tracks referred to as Rhinoceripeda voconcense (Demathieu et al., 1984 Demathieu, G., Ginsburg, L., Guérin, C. and Truc, G. 1984. Etude paléontologique, ichnologique et paléoécologique du gisement oligocène de Saignon (bassin d’Apt, Vaucluse). Bulletin du Museum National d’Histoire Naturelle, Paris, 6: 153–183.  [Google Scholar]), artiodactyls footprints referred to as Megapecoripeda velox (Demathieu et al., 1984 Demathieu, G., Ginsburg, L., Guérin, C. and Truc, G. 1984. Etude paléontologique, ichnologique et paléoécologique du gisement oligocène de Saignon (bassin d’Apt, Vaucluse). Bulletin du Museum National d’Histoire Naturelle, Paris, 6: 153–183.  [Google Scholar]) and a carnivore footprint referred to as Bestiopeda sp. Vialov (1966) Vialov, O. S. 1966. Sledy zhiznedeyatelnosti organizmow i ikh paleontologicheskoe znachenie. Naukova Dumka, : 219 (in Russian) [Google Scholar]. They can be attributed to early Rhinocerotids, Lophiomerycids and/or Entelodonts and Mustelid-like carnivore, respectively. This study also aims at homogenizing the ichnotaxonomy used for mammal tracks where several genera were erected without a full review of the literature. All this taken together reveals a rich mammalian ichnofauna at a time period when no other fossils of mammals are known in the area and represents a good opportunity to provide state-of-the-art concerning the worldwide known sites that yielded mammalian footprints.     

175 Structure-based engineering to generate high-affinity immunotherapy for the drug of abuse

Methamphetamine (METH) abuse is a major threat in the USA and worldwide without any FDA approved medications. Anti-METH antibody antagonists block or slow the rate of METH entry into the brain and have shown efficacy in preclinical studies (Peterson, Laurenzana, Atchley, Hendrickson, & Owens, 2008 Peterson, E. C., Laurenzana, E. M., Atchley, W. T., Hendrickson, H. P. and Owens, S. M. 2008. Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine. Journal of Pharmacology and Experimental Therapeutics, 08: 124–133.  [Google Scholar]).?A key determinant of the antibody’s efficacy is its affinity for METH and we attempted to enhance the efficacy by designing mutations to alter the shape or the electrostatic character of the binding pocket. Towards this goal, we developed a single chain anti-METH antibody fragment (scFv6H4) from a parent IgG (1). The crystal structure of scFv-6H4 in complex with METH was determined (Celikel, Peterson, Owens, & Varughese, 2009 Celikel, R., Peterson, E. C., Owens, S. M. and Varughese, K. I. 2009. Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse-Methamphetamine and 3,4-methylenedioxymethamphetamine. Protein Science, 09: 2336–2345.  [Google Scholar]). Based on its elucidated binding interactions, we designed point mutations in the binding pocket to improve its affinity for METH and amphetamine (AMP), the active metabolite of METH. The mutants, scFv-S93T,-I37?M and -Y34?M were cloned, expressed in yeast and tested for affinity against METH and AMP. Two mutants showed enhanced binding affinity for METH: scFv-I37?M by 1.3-fold and scFv-S93T by 2.6-fold. Additionally, all the mutants showed increase in affinity for AMP: scFv-I37?M by 56-fold, scFv-S93T by 17-fold and scFvY34?M by 5-fold. Crystal structure for one of the high-affinity mutant, scFv-S93T, in complex with METH was determined (Figure 1). Binding pocket of the mutant is more hydrophobic in comparison with the wild type. ScFv-6H4 binds METH in a deep pocket containing two water molecules. The substitution of a serine residue by a threonine leads to the expulsion of a water molecule (Figure 2), relieving some unfavorable contacts between the hydrocarbon atoms of METH and the water molecule and increasing the affinity to sub-nanomolar range. Therefore, the present study shows that efficacy could be enhanced by altering the hydrophobicity or the shape of the binding pocket.     

EFFICIENT SYNTHESIS OF FUSED ISOTHIAZOLO C-NUCLEOSIDES. III. SYNTHESIS OF 7-SUBSTITUTED ISOTHIAZOLO[4,5-d]PYRIMIDINE C-NUCLEOSIDES*

The Divakar-Reese procedure has been successfully applied for transforming 7-oxo-isothiazolo[4,5-d]pyrimidine C-nucleosides (4a,b, 5a,b, 6a) via 1,2,4-triazol-1-yl intermediates (7a,b, 8a,b) into various 7-substituted C-nucle- osides 15a,b, 16a,b, 17a, 18a, 19a,b, 20a,b; their subsequent deprotection provides novel types of unusual C-glycosides 22b, 23a, 24a,b, 25b, 26b.

C-Nucleosides, possessing on its heterocyclic base other than naturally occuring oxo- or amino substituents, are important model compounds for biological or medicinal studies [2a] Hanessian, S. and Pernet, A. G. 1976. Adv. Carbohydr. Chem. Biochem., 32: 111–188. cf. [Google Scholar], [2b] Mizuno, Y. 1986. The Organic Chemistry of Nucleic Acids Amsterdam: Elsevier.  [Google Scholar], [2c] Huryn, D. M. and Okabe, M. 1992. Chem. Rev., 92: 1745–1768. [Crossref], [Web of Science ®] , [Google Scholar], [2d] Häbich, D. 1991. Chem. in uns. Zeit, 25: 295–307.  [Google Scholar], [2e] Uhlmann, E. and Peyman, A. 1990. Chem. Rev., 90: 543–584. [Crossref], [Web of Science ®] , [Google Scholar], [2f] Thuong, N. T. and Helene, C. 1993. Angew. Chem., 105: 697–723. [Crossref] , [Google Scholar], [2g] 1993. Angew. Chem. Int. Ed. Engl., 33: 666–690.  [Google Scholar], [2h] Yarchoan, R., Mitsuya, H., Zhomas, R. V., Pluda, J. M., Hartman, N. R., Perno, C. F., Marczyk, K. S., Allain, J. P., Johns, D. G. and Broder, S. 1989. Science, 245: 412–414. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar], [2i] Tanaka, H., Baba, M., Hayakawa, H., Sakamaki, T., Miyasaka, T., Ubasawa, M., Takashima, H., Sekiya, E., Nitta, I., Shigeta, S., Walker, R. T., Balzarini, J. and De Clerq, E. 1991. J. Med. Chem., 34: 349–357. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar] [3a] Koyama, G., Maeda, K., Umezawa, H. and Iitaka, Y. 1966. Tetrahedron Lett., : 597–602. Some C-glycosides with antibiotic, antiviral (HIV), and anticancer activities [Google Scholar], [3b] Hori, M., Wakashiro, T., Ito, E., Sawa, T., Takeuchi, T. and Umezawa, H. J. 1968. J. Antibiot., 21A: 264–270. [Chem. Abstr. 1968, 69, 11356j] [Google Scholar], [3c] Farkas, J. and ?orm. 1972. F. Collect. Czech. Chem. Commun., 37: 2798–2803.  [Google Scholar], [3d] Acton, E. M., Ryan, K. J., Henry, D. W. and Goodman, L. 1971. J. Chem. Soc., Chem. Commun., : 986–988.  [Google Scholar], [3e] Nakagawa, Y., Kano, H., Tsukuda, Y. and Koyama, H. 1967. Tetrahedron Lett., : 4105–4109.  [Google Scholar], [3f] Inoue, I. and Kuwaijama, I. 1980. J. Chem. Soc., Chem. Commun., : 251–253.  [Google Scholar], [3g] Buchanan, J. G., Stobie, A. and Wightman, R. H. 1980. ibid., : 916–917. [Crossref] , [Google Scholar], [3h] Hildebrand, S. and Leumann, C. 1996. Angew. Chem., 108: 2100–2102. Angew. Chem. Int. Ed. Engl. 1996, 35, 1968–1970 [Google Scholar]. We want to report on the synthesis of novel 7-substituted isothiazolo = [4,5-d]pyrimidine C-nucleosides. As we could show in previous papers [1] Wamhoff, H., Berressem, R. and Nieger, M. 1994. J. Org. Chem., 59: 1912–1917. Part 2 [Google Scholar], [4] Wamhoff, H., Berressem, R. and Nieger. 1993. M. J. Org. Chem., 58: 5181–5185.  [Google Scholar], there exists a simple approach to the protected C-glycosides 4–6.

     

New software for finding transition states by probing accessible,or ergodic,regions

An automated, iterative approach to finding the lowest energy, ionic diffusion paths through a periodic structure has been developed within our new code (written in FORTRAN 77 and named Bubble). The approach is quite general in that it can be applied to find, at a chosen temperature, the accessible (ergodic) regions of a hyper-surface, which is defined across a uniform grid [1 Schön, J.C., Putz, H. and Jansen, M. 1996. Studying the energy hypersurface of continuous system—The threshold algorithm. J. Phys.-Conden. Matt., 8: 143[Crossref] , [Google Scholar]]. We describe both our implementation within the Bubble code and its application to locating the approximate transition states for Mg interstitial diffusion in forsterite, which can then be refined using standard transition state searching [2 Banerjee, A., Adams, N., Simons, J. and Shepard, R. 1985. Search for stationary points on surfaces. J. Phys. Chem., 89: 52[Crossref], [Web of Science ®] , [Google Scholar]].     

An Efficient Alternative Route To 3,6-Disubstituted-Furo[2,3-d]Pyrimidin-2-One Analogues

Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrimidin-2-one analogues.     

158 A molecular dynamics simulation-based prediction of deleterious angiogenin mutations causing amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons leading to paralysis and death between 3–5?years of diagnosis. Through whole genome association studies, several single nucleotide polymorphisms (SNPs) encoding missense mutations in angiogenin (ANG) protein have been identified as one of the primary factors causing ALS. Structural studies of ANG show that catalytic triad comprising His13, Lys40, and His114 residues imparts ribonucleolytic activity while nuclear localization signal residues ³¹RRR³³ are responsible for nuclear translocation activity. Loss of either ribonucleolytic activity or nuclear translocation activity or both of these functions due to mutations cause ALS. However, the mechanisms of loss-of-functions of ANG mutants are not completely understood. Here, we present a cohesive and comprehensive picture of functional loss mechanisms of all known ALS-associated ANG mutants by extensive molecular dynamics (MD) simulations (Padhi, Kumar, Vasaikar, Jayaram, & Gomes, 2012 Padhi, A. K., Kumar, H., Vasaikar, S. V., Jayaram, B. and Gomes, J. 2012. Mechanisms of loss of functions of human angiogenin variants implicated in amyotrophic lateral sclerosis. PLoS One, 7(2): e32479[PubMed] , [Google Scholar]; AK, 2013 Padhi, A.K., Jayaram, B., & Gomes, J. (accepted for publication). Prediction of functional loss of human angiogenin mutants associated with ALS by molecular dynamics simulations. Scientific Reports (NPG).  [Google Scholar]). Our studies show that conformational switching of catalytic residue His114 is responsible for the loss of ribonucleolytic activity while reduction in solvent-accessible surface area (SASA) of ³¹RRR³³ as a result of local folding is responsible for the loss of nuclear translocation activity (Padhi et al., 2012 Padhi, A. K., Kumar, H., Vasaikar, S. V., Jayaram, B. and Gomes, J. 2012. Mechanisms of loss of functions of human angiogenin variants implicated in amyotrophic lateral sclerosis. PLoS One, 7(2): e32479[PubMed] , [Google Scholar]; AK, 2013 Padhi, A.K., Jayaram, B., & Gomes, J. (accepted for publication). Prediction of functional loss of human angiogenin mutants associated with ALS by molecular dynamics simulations. Scientific Reports (NPG).  [Google Scholar]). Our prediction of loss-of-functions of 17 ANG mutants correlated positively with the reported experimental results. We have subsequently developed a fast molecular dynamics method based on certain global attributes / dynamic markers that can be used to determine whether a mutation is deleterious or benign. To make our method accessible to researchers and clinicians, we created a web server-based tool, ANGDelMut, freely available at http://bioschool.iitd.ernet.in/research.htm, where a user can submit new mutations to ascertain whether they cause ALS. We hope that our method will benefit the community at large and will pave the way for the development of a successful therapy for patients suffering from ALS.     

On several conjectures from evolution of dispersal

We address several conjectures raised in Cantrell et al. [Evolution of dispersal and ideal free distribution, Math. Biosci. Eng. 7 (2010), pp. 17–36 [9 Cantrell, R. S., Cosner, C. and Lou, Y. 2010. Evolution of dispersal and ideal free distribution. Math. Biosci. Eng., 7: 17–36. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]] concerning the dynamics of a diffusion–advection–competition model for two competing species. A conditional dispersal strategy, which results in the ideal free distribution of a single population at equilibrium, was found in Cantrell et al. [9 Cantrell, R. S., Cosner, C. and Lou, Y. 2010. Evolution of dispersal and ideal free distribution. Math. Biosci. Eng., 7: 17–36. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]. It was shown in [9 Cantrell, R. S., Cosner, C. and Lou, Y. 2010. Evolution of dispersal and ideal free distribution. Math. Biosci. Eng., 7: 17–36. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]] that this special dispersal strategy is a local evolutionarily stable strategy (ESS) when the random diffusion rates of the two species are equal, and here we show that it is a global ESS for arbitrary random diffusion rates. The conditions in [9 Cantrell, R. S., Cosner, C. and Lou, Y. 2010. Evolution of dispersal and ideal free distribution. Math. Biosci. Eng., 7: 17–36. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]] for the coexistence of two species are substantially improved. Finally, we show that this special dispersal strategy is not globally convergent stable for certain resource functions, in contrast with the result from [9 Cantrell, R. S., Cosner, C. and Lou, Y. 2010. Evolution of dispersal and ideal free distribution. Math. Biosci. Eng., 7: 17–36. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]], which roughly says that this dispersal strategy is globally convergent stable for any monotone resource function.     

Small Amphibian and Reptile Footprints from the Permian Carapacha Basin,Argentina

This paper contains a taxonomic study of the Permian tetrapod ichnofauna from the Carapacha Basin. Tetrapod traces are analyzed in their environmental context and compared with similar faunas from Europe and North America. This ichnofauna is particularly relevant because of the scarcity of Permian tetrapod tracks from South America and also of Permian tetrapod fossils from Argentina. Ephemeral fluvial and shallow lacustrine deposits compose the sedimentary succession of the basin, which is represented by the Carapacha Formation. Most of the tracks have been collected from the upper member of the formation (Urre-Lauquen Member), mainly from freshwater ephemeral lake deposits as well as from playa-lake mudflats. The deposits of this member have been attributed to the early Late Permian on the basis of a Glossopteris fossil flora. Ichnotaxonomic designations of tetrapod traces are made on the basis of morphologic features that reflect the anatomy of the producer and special attention has been paid to extramorphologic deformations observed in the track assemblage. A total of four footprint ichnotaxa have been recognized, namely Batrachichnus salamandroides (Geinitz, 1861 Geinitz, H. B. 1861. Dyas oder die Zechsteinformation und das Rhotliegende—Die animalischen Überreste der Dyas, 130 ppLeipzig: Wilhelm Engelmann.  [Google Scholar]), Hyloidichnus bifurcatus Gilmore, 1927 Gilmore, C. W. 1927. Fossil footprints from the Grand Canyon: second contribution. Smithsonian Miscellaneous Collection, 80(3): 1–78.  [Google Scholar], cf. Amphisauropus isp. and cf. Varanopus isp. These track taxa are associated with two forms of vertebrate swimming traces (Characichnos isp. and type A swimming trace) and a possible fish trail. Invertebrate trace fossils include abundant arthropod locomotion traces and Scoyenia isp. The ichnofauna is composed of six tetrapod ichnocoenoses that are dominated by tiny amphibian tracks attributed to Temnospondyli (Batrachichnus and type A swimming trace) and Seymouriamorpha (Amphisauropus), and also contain the footprints of small reptiles, mostly Captorhinomorpha and possibly Pelycosauria (Hyloidichnus and Varanopus). Even if the ichnofauna of the Carapacha Basin is slightly younger than typical examples from the literature of the Early Permian “red bed ichnofacies” (Hunt et al., 1995b Hunt, A. P., Lucas, S. G., Lockley, M. G., Haubold, H. and Braddy, S. 1995b. Tetrapod ichnofacies in Early Permian red beds of the American Southwest. Bulletin New Mexico Museum of Natural History and Science, 6: 295–301. Early Permian footprint facies [Google Scholar]), a comparison is made. However, further detailed case studies are needed to formally define this “red bed ichnofacies” and its prospective subdivisions.     

New Important Iguanodontid and Theropod Trackways of the Tracksite Obernkirchen in the Berriasian of NW Germany and Megatracksite Concept of Central Europe

This article examines the high-resolution track horizon stratigraphy at the outcrop Obernkirchen. Massive sandstones, products of marine sand bar and fluviatile environments are present at the tracksite. Recently two track beds were examined in the outcrop. One new track slab of the lower track bed is described exposing well-preserved quadrupedal iguanodontid tracktypes of Iguanodontipus Sarjeant, Delair, and Lockley, 1998 Sarjeant, W. A. S., Delair, J. B. and Lockley, M. G. 1998. The footprints of Iguanodon: a history and taxonomic study. Ichnos, 6: 183–202. [Taylor & Francis Online] , [Google Scholar], and bipedal theropod tracks Megalosauropus Kaever and Lapparent, 1974 Kaever, M. and Lapparent, A. F. de. 1974. Les traces des pas le Dinosaures du Jurassique des Barkhausen (Basse Saxe, Allemagne). Bulletin de la Societé Geologique Français, 16: 516–525.  [Google Scholar]. The ichnogenus Iguanodontipus is discussed and the diagnosis extended. The tracksite Obernkirchen belongs to a megatracksite of the ancient coastline of the marginal marine Hercynic Basin of the Lower Cretaceous of Europe, including the four well-known sites Obernkirchen, Bad Rehburg, Münchehagen, and Bückeburg of Northwest Germany. Three different tracktypes of huge sauropods, theropods, and ornithopods are abundant at basal Lower Cretaceous siliciclastic coastlines in different regions in Spain, Portugal, England, Germany, and Switzerland. Dinosaur tracks are also present in carbonate platform environments of northern Italy and Istria.     

A Life-History Model of Human Fitness Indicators

Recent adaptationist accounts of human mental and physical health have reinvigorated the debate over the evolution of human intelligence. In the tradition of strong inference the current study was developed to determine whether either Miller's (1998 Miller, G. F. 1998. “How mate choice shaped human nature: A review of sexual selection and human evolution”. In Handbook of evolutionary psychology: Ideas, issues, and applications, Edited by: Crawford, C. and Krebs, D. 87–129. Hillsdale, NJ: Lawrence Erlbaum.  [Google Scholar], 2000a Miller, G. F. 2000a. Mental traits as fitness indicators: Expanding evolutionary psychology's adaptationism. Evolutionary approaches to human reproductive behavior. Ann N Y Acad Sci, 907: 62–74. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) Fitness Indicator Theory or Rushton's (1985 Rushton, J. P. 1985. Differential K theory: The sociobiology of individual and group differences. Pers Indiv Diff, 6(4): 441–452. [Crossref] , [Google Scholar], 2000 Rushton, J. P. 2000. Race, evolution, and behavior: A life-history perspective, 3rd, Port Huron, MI: Charles Darwin Research Institute.  [Google Scholar]) Differential-K Theory better accounts for general intelligence (“g”) in an undergraduate university population (N = 192). Owing to the lengthy administration time of the test materials, a newly developed 18-item short form of the Ravens Advanced Progressive Matrices (APM-18; Sefcek, Miller, and Figueredo 2007 Sefcek, J. A., Miller, G. F. and Figueredo, A. J. 2007. “Development and of an 18-item short form of the Ravens Advanced Progressive Matrices (RAPM-18). (Submitted)”.  [Google Scholar]) was used. A significant, positive relationship between K and F (r = .31, p < .001) emerged. Contrary to predictions, no significant relationships were found between “g” and either K or F (r = –.09, p ≥ .05 and r = .11, p ≥ .05, respectively). Though generally contrary to both hypotheses, these results may be explained in relation to antagonistic pleiotropy and a potential failure to derive correct predictions for within-species comparisons directly from the results of between-species comparisons.     

Redefinition of the hypotrichous ciliate Uncinata,with descriptions of the morphology and phylogeny of three urostylids (Protista,Ciliophora)

We investigated the morphology, morphogenesis and small subunit rRNA gene-based phylogeny of three marine urostylids, Uncinata gigantea Bullington, 1940 Bullington, W. E. (1940). Some ciliates from Tortugas. Papers from the Tortugas Laboratory, 32, 179–221. [Google Scholar], Holosticha heterofoissneri Hu & Song, 2001 Hu, X., & Song, W. (2001). Morphology and morphogenesis of Holosticha heterofoissneri n. sp. from the Yellow Sea, China (Ciliophora, Hypotrichida). Hydrobiologia, 448, 171–179. doi:10.1023/A:1017553406031.[Crossref], [Web of Science ®] , [Google Scholar], and Holosticha cf. heterofoissneri. The dorsal morphogenesis of Uncinata gigantea shows de novo formation of two groups of anlagen near the marginal rows. Holosticha cf. heterofoissneri demonstrates fragmentation of the first dorsal kinety anlage as in Holosticha heterofoissneri. Our population of H. heterofoissneri corresponds well with previously described populations in terms of its general morphology and ciliary pattern. Uncinata gigantea can be recognized by its large and highly contractile body, yellowish to brownish cell colour, two types of cortical granules, and 20–30 transversely oriented and densely arranged cirri in the left marginal row, which often overlie the buccal vertex. Based on the new data, especially infraciliature, the genus Uncinata is here redefined. Both the morphology and phylogenetic analyses suggest that the genus Uncinata should be classified within the family Urostylidae. In addition, both morphological and morphogenetic data suggest that Holosticha bradburyae Gong et al., 2001 Gong, J., Song, W., Hu, X., Ma, H., & Zhu, M. (2001). Morphology and infraciliature of Holosticha bradburyae n. sp. (Ciliophora, Hypotrichida) from the Yellow Sea, China. Hydrobiologia, 464, 63–69. doi:10.1023/A:1013901621439.[Crossref], [Web of Science ®] , [Google Scholar] should be transferred to Uncinata as U. bradburyae (Gong et al., 2001 Gong, J., Song, W., Hu, X., Ma, H., & Zhu, M. (2001). Morphology and infraciliature of Holosticha bradburyae n. sp. (Ciliophora, Hypotrichida) from the Yellow Sea, China. Hydrobiologia, 464, 63–69. doi:10.1023/A:1013901621439.[Crossref], [Web of Science ®] , [Google Scholar]) comb. nov., due to its possession of a characteristically prominent beak-like, leftwards curved projection and the developmental mode of the dorsal kineties. This assignment is supported by the phylogenetic analyses, which placed Uncinata gigantea in a clade with U. bradburyae (Gong et al., 2001 Gong, J., Song, W., Hu, X., Ma, H., & Zhu, M. (2001). Morphology and infraciliature of Holosticha bradburyae n. sp. (Ciliophora, Hypotrichida) from the Yellow Sea, China. Hydrobiologia, 464, 63–69. doi:10.1023/A:1013901621439.[Crossref], [Web of Science ®] , [Google Scholar]) comb. nov., and revealed only 1.13% (19 bp) difference in their SSU-rDNA gene sequence.     

Animal-Facilitated Therapy Revisited

In Disney/Pixar's phenomenally popular animated film Finding Nemo (Stanton, 2003 Stanton, A. Writer/Director. 2003. Finding Nemo [Motion picture], United States: Pixar Animation Studios.  [Google Scholar]), one of the central themes of fish welfare was highlighted when the moorish idol, Gill, commented, “Fish aren't meant to be kept in a box, kid. It does things to you.” The notion that fish might have the capacity to suffer in captivity (Chandroo, Duncan, & Moccia, 2004a Chandroo, K. P., Duncan, I. J. H and Moccia, R. D. 2004a. Can fish suffer?: Perspectives on sentience, pain, fear and stress. Applied Animal Behaviour Science, 86: 225–250. [Crossref], [Web of Science ®] , [Google Scholar], 2004b Chandroo, K. P., Duncan, I. J. H and Moccia, R. D. 2004b. An evaluation of current perspectives on consciousness and pain in fish. Fish and Fisheries, 5: 281–295. [Crossref], [Web of Science ®] , [Google Scholar]) links to the larger question of sentiency, which remains a fundamental tenet when justifying concerns for nonhuman animal welfare (Dawkins, 2006 Dawkins, M. S. 2006. Through animal eyes: What behaviour tells us. Applied Animal Behaviour Science, 100: 4–10. [Crossref], [Web of Science ®] , [Google Scholar]; Huntingford et al., 2006 Huntingford, F. A., Adams, C., Braithwaite, V. A., Kadri, S., Pottinger, T. G.Sandoe, P. 2006. Review paper: Current issues in fish welfare. Journal of Fish Biology, 68: 332–372. [Crossref], [Web of Science ®] , [Google Scholar]). Although terrestrial nonhuman-animal welfare has been discussed and explored for many years, the development of aquatic animal welfare concepts and approaches remains relatively new and beyond public awareness (Braastad, Damsgård, & Juell, 2006; Broom, 2007 Broom, D. M. 2007. Cognitive ability and sentience: Which aquatic animals should be protected?. Disease of Aquatic Organisms, 75: 99–108. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]; Farmed Animal Welfare Council, 1996; Fisheries Society of the British Isles, 2002; Håstein, Scarfe, & Lund, 2005; Iwama, 2007 Iwama, G. K. 2007. The welfare of fish. Diseases of Aquatic Organisms, 75: 155–158. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]; Schreck, 1981 Schreck, C. B. 1981. “Stress and compensation in teleostean fishes: Response to social and physical factors”. In Stress and fish, Edited by: Pickering, A. D. 295–321. London: Academic.  [Google Scholar]).     

Toxicological Approach for Assessing the Heavy Metal Binding Capacity of Soils

A toxicological approach was taken to determine the heavy metal binding capacity of soils. A soil heavy metal binding capacity (SHMBC) methodology was developed and was based on the use of the MetPLATE ^TM toxicity test kit, a bioassay that is specific for heavy metal toxicity. SHMBC test is based on the heavy metal binding capacity (HMBC) concept that has been considered in the assessment of the metal binding capacity of surface waters (Huang et al., 1999 Huang, F., Bitton, G. and Kong, I.-C. 1999. Determination of the heavy metal binding capacity of aquatic samples using MetPLATE?: a preliminary study. Sci. Total Environ, 234: 139–145.  [Google Scholar]) and solid wastes landfill leachates (Ward et al., 2005 Ward, M., Bitton, G. and Townsend, T. 2005. Heavy metal binding capacity (HMBC) of municipal solid waste landfill leachates. Chemosphere, 60: 206–215. [Crossref], [PubMed], [Web of Science ®] [Google Scholar]). SHMBC is the ratio of the EC ₅₀ of an added metal in a soil sample divided by the EC ₅₀ of a metal in a reference soil (clean Ottawa sand). A higher SHMBC value indicates higher metal binding to soil and lower bioavailability and potential toxicity to the test bacteria.

Five soils (two sandy soils, two organic soils and a clay soil) were used to determine their binding capacity towards Cu, Zn, and Hg, using the developed SHMBC test. The test measured the ability of the solids to reduce metal bioavailability and toxicity. SHMBC was highest for the clay soil and lowest for the sandy soils. The potential application of this relatively rapid (a few hours) test to predict metal toxicity to terrestrial plants is discussed.     

Teaching music in the flat world: Reflections on the work of Darling-Hammond and Rothman

Authors and scholars published within Arts Education Policy Review have been diligent to investigate various topics surrounding music educator preparation, mentoring, retention, as well as avenues for continued professional development and growth. Linda Darling-Hammond and Robert Rothman, along with various chapter authors, address education reform on an international level within Teaching in the Flat World: Learning from High-Performing Systems (2015 Rothman, R., & Darling-Hammond, L. (2015). Teaching quality initiatives in the United States. In L. Darling-Hammond & R. Rothman (Eds.), Teaching in the flat world: Learning from high-performing systems (pp. 6–27). New York, NY: Teachers College Press. [Google Scholar]). The purpose of this article is to examine the recommendations presented by Darling-Hammond, Rothman, and colleagues through the lens of music education research and policy review. Specific areas of focus include: (a) recruitment and rigor of teacher education programs, (b) alternative routes into the teaching profession, (c) teacher induction and new teacher support, (d) career advancement and professional development support, and (e) teacher evaluation.     

Capillary Effects on Natural Remobilization of Pools of Dense Non-Aqueous Phase Liquid Mixtures in Porous Media

The natural remobilization of an initially static mixed dense non-aqueous phase liquid (DNAPL) pool due to dissolution was demonstrated by (Roy et al. 2002 Roy, J. W., Smith, J. E. and Gillham, R. W. 2002. Natural remobilization of multicomponent DNAPL pools due to dissolution. J. Contam. Hydrol., 59: 163–186. [Crossref], [PubMed], [Web of Science ®] [Google Scholar], 2004 Roy, J. W., Smith, J. E. and Gillham, R. W. 2004. Laboratory evidence of natural remobilization of multicomponent DNAPL pools due to dissolution. J. Contam. Hydrol., 74: 145–161. [Crossref], [PubMed], [Web of Science ®] [Google Scholar]) using a compositional mathematical model and laboratory experiments with open pools over a porous medium. The purposes of this study were to: a) demonstrate natural remobilization for a pool within porous media (as opposed to an open pool); and b) analyze the capillary effects associated with residual formation, a changing saturation profile, hysteresis, and aging, as these processes may reduce the potential for natural remobilization of pools in porous media. DNAPL pools comprised of tetrachloroethene and benzene were created within a zone of larger glass beads overlying smaller glass beads, in a water-saturated 2-D flow cell. In one case, remobilization occurred in the form of a DNAPL finger, after 56 days of flushing. In another case, no remobilization had occurred after 64 days of flushing, though the density increased by 430 kg m ^?3 and remobilization was predicted by the compositional model. Comparison of observations with model predictions suggest that contact angle hysteresis, related to an observed change in wettability, was the most significant contributing factor causing overprediction of the potential for natural remobilization.     

Translational control of gurken mRNA in Drosophila development

Localized mRNA translation is a widespread mechanism for targeting protein synthesis, important for cell fate, motility and pathogenesis. In Drosophila, the spatiotemporal control of gurken/TGF-α mRNA translation is required for establishing the embryonic body axes. A number of recent studies have highlighted key aspects of the mechanism of gurken mRNA translational control at the dorsoanterior corner of the mid-stage oocyte. Orb/CPEB and Wispy/GLD-2 are required for polyadenylation of gurken mRNA, but unlocalized gurken mRNA in the oocyte is not fully polyadenylated.¹ Norvell A, Wong J, Randolph K, Thompson L. Wispy and Orb cooperate in the cytoplasmic polyadenylation of localized gurken mRNA. Dev Dyn Off Publ Am Assoc Anat 2015; 244:1276-1285. [Google Scholar] At the dorsoanterior corner, Orb and gurken mRNA have been shown to be enriched at the edge of Processing bodies, where translation occurs.² Weil TT, Parton RM, Herpers B, Soetaert J, Veenendaal T, Xanthakis D, Dobbie IM, Halstead JM, Hayashi R, Rabouille C, et al. Drosophila patterning is established by differential association of mRNAs with P bodies. Nat Cell Biol 2012; 14:1305-1313; PMID:23178881; http://dx.doi.org/10.1038/ncb2627[Crossref], [PubMed], [Web of Science ®] [Google Scholar] Over-expression of Orb in the adjacent nurse cells, where gurken mRNA is transcribed, is sufficient to cause mis-expression of Gurken protein.³ Davidson A, Parton RM, Rabouille C, Weil TT, Davis I. Localized translation of gurken/TGF-α mRNA during axis specification is controlled by access to Orb/CPEB on processing bodies. Cell Rep 2016; 14:2451-2462; PMID:26947065; http://dx.doi.org/10.1016/j.celrep.2016.02.038[Crossref], [PubMed], [Web of Science ®] [Google Scholar] In orb mutant egg chambers, reducing the activity of CK2, a Serine/Threonine protein kinase, enhances the ventralized phenotype, consistent with perturbation of gurken translation.⁴ Wong LC, Costa A, McLeod I, Sarkeshik A, Yates J 3rd, Kyin S, Perlman D, Schedl P, et al. The functioning of the drosophila CPEB protein Orb is regulated by phosphorylation and requires casein kinase 2 activity. PLoS One 2011; 6:e24355; PMID:21949709; http://dx.doi.org/10.1371/journal.pone.0024355[Crossref], [PubMed], [Web of Science ®] [Google Scholar] Here we show that sites phosphorylated by CK2 overlap with active Orb and with Gurken protein expression. Together with our new findings we consolidate the literature into a working model for gurken mRNA translational control and review the role of kinases, cell cycle factors and polyadenylation machinery highlighting a multitude of conserved factors and mechanisms in the Drosophila egg chamber.