Functions of prion protein PrPc

It is now well established that both normal and pathological (or scrapie) isoforms of prion protein, PrPc and PrPsc respectively, are involved in the development and progression of various forms of neurodegenerative diseases, including scrapie in sheep, bovine spongiform encephalopathy (or "mad cow disease") and Creutzfeldt-Jakob disease in human, collectively known as prion diseases. The protein PrPc is highly expressed in the central nervous system in neurons and glial cells, and also present in non-brain cells, such as immune cells or epithelial and endothelial cells. Identification of the physiological functions of PrPc in these different cell types thus appears crucial for understanding the progression of prion diseases. Recent studies highlighted several major roles for PrPc that may be considered in two major domains : (1) cell survival (protection against oxidative stress and apoptosis) and (2) cell adhesion. In association with cell adhesion, distinct functions of PrPc were observed, depending on cell types : neuronal differentiation, epithelial and endothelial barrier integrity, transendothelial migration of monocytes, T cell activation. These observations suggest that PrPc functions may be particularly relevant to cellular stress, as well as inflammatory or infectious situations.     

A Miocene hyperdiverse crocodylian community reveals peculiar trophic dynamics in proto-Amazonian mega-wetlands

Amazonia contains one of the world''s richest biotas, but origins of this diversity remain obscure. Onset of the Amazon River drainage at approximately 10.5 Ma represented a major shift in Neotropical ecosystems, and proto-Amazonian biotas just prior to this pivotal episode are integral to understanding origins of Amazonian biodiversity, yet vertebrate fossil evidence is extraordinarily rare. Two new species-rich bonebeds from late Middle Miocene proto-Amazonian deposits of northeastern Peru document the same hyperdiverse assemblage of seven co-occurring crocodylian species. Besides the large-bodied Purussaurus and Mourasuchus, all other crocodylians are new taxa, including a stem caiman—Gnatusuchus pebasensis—bearing a massive shovel-shaped mandible, procumbent anterior and globular posterior teeth, and a mammal-like diastema. This unusual species is an extreme exemplar of a radiation of small caimans with crushing dentitions recording peculiar feeding strategies correlated with a peak in proto-Amazonian molluscan diversity and abundance. These faunas evolved within dysoxic marshes and swamps of the long-lived Pebas Mega-Wetland System and declined with inception of the transcontinental Amazon drainage, favouring diversification of longirostrine crocodylians and more modern generalist-feeding caimans. The rise and demise of distinctive, highly productive aquatic ecosystems substantially influenced evolution of Amazonian biodiversity hotspots of crocodylians and other organisms throughout the Neogene.     

Low- to high-throughput analysis of telomerase modulators with Telospot

We designed a method termed Telospot to discover and characterize telomerase modulators as anticancer drugs or chemical biology tools. Telospot is based on a highly efficient human telomerase expression system and the detection of telomerase DNA reaction products in macroarray format. Telospot offers a highly scalable, cost- and time-effective alternative to presently available telomerase assays, which are limited by the requirement for PCR, telomerase purification or technologies not amenable to high throughput.     

Enamel microstructure defines a major Paleogene hippopotamoid clade: the Merycopotamini (Cetartiodactyla,Hippopotamoidea)

We present new material of the selenodont anthracothere Hemimeryx blanfordi from the Oligocene deposits of the Bugti Hills (Balochistan, Pakistan), collected between 1999 and 2002. This is the first undisputed Oligocene occurrence of the species, previously known from the early Miocene of Pakistan. Investigation of the molar enamel microstructure reveals a surprising mono-zonal Schmelzmuster, already detected in some middle to Late miocene selenedont anthracotheres. We include this observation combined with a morphological revision of H. blanfordi and a cladistic assessment of the dental evidence, to propose a new phylogenetic hypothesis regarding Hemimeryx and its close relatives. We confirm the clade including advanced bothriodontines, which we erect to a tribe rank and name Merycopotamini. The South Asian origin of Merycopotamini is consistent with hypothesized subsequent dispersal events of Merycopotamini from Asia to Africa.     

Western Amazonia as a Hotspot of Mammalian Biodiversity Throughout the Cenozoic

A state-of-the-art review of the Cenozoic fossil record from Western Amazonia is provided, based on literature and new data (regarding Paleogene native ungulates). It allows summarizing the evolution and dynamics of middle Eocene–Holocene mammalian guilds, at the level of species, families, and orders. Major gaps in the Western Amazonian mammal record occur in the pre-Lutetian and early Miocene intervals, and in the Pliocene epoch. Twenty-three orders, 89 families, and 320 species are recognized in the fossil record, widely dominated by eutherians from the middle Eocene onward. Probable Allotheria (Gondwanatheria) occur only in the earliest interval, whereas Metatheria and Eutheria are conspicuous components of any assemblage. Taxonomic diversity was probably fairly constant at the ordinal level (~12–14 orders in each time slice considered) and much more variable in terms of family and species richness: if most intervals are characterized by 40–50 co-occurring species and 19–31 co-occurring families, the early Miocene period illustrates a depauperate fauna (21 species, 17 families), strongly contrasting with the late Miocene climactic guild (82 species, 38 families). Recent mammalian taxonomic diversity from Western Amazonia (12 orders, 37 families, and 286 species) is at odds with all past intervals, as it encompasses only three orders of South American origin (Didelphimorphia, Cingulata, and Pilosa) but four North American immigrant orders (Artiodactyla, Perissodactyla, Carnivora, and Lagomorpha). In terms of taxonomic diversity, recent mammalian guilds are fully dominated by small-sized taxa (Chiroptera, Rodentia, and Primates). This overview also confirms the scarcity of large mammalian flesh-eaters in ancient Neotropical mammalian assemblages. The pattern and the timing of mammalian dispersals from northern landmasses into Western Amazonia are not elucidated yet.     

Cenozoic Evolution of TRopical-Equatorial MAmmals (TREMA)–an Introduction to the Symposium Proceedings Volume

This special issue of the Journal of Mammalian Evolution coincides with the proceedings from a symposium held in conjunction with the 4th International Palaeontological Congress (IPC4, Mendoza, Argentina; September 28, 2014), entitled “Cenozoic evolution of TRopical-Equatorial MAmmals,” and abbreviated as TREMA. In this short introduction to the symposium proceedings, in which we present the contents of the current issue, we discuss the pivotal role of the mammalian fossil record at low latitudes for understanding the origin, structural organization, and dynamics of present mammalian biodiversity.     

Use of conformationally constrained peptides for a topographical analysis of the combining site of a monoclonal anti-substance P antibody

The topography of the binding site of a monoclonal anti-substance P antibody directed toward the C-terminal pentapeptide of substance P, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂, was analyzed further using a wide range of constrained analogues of substance P. Results obtained in the present study show the following: (a) The binding subsites of Phe⁷ and Phe⁸ are large and deep, accommodating various side chains, including nonaromatic amino acids. (b) In contrast, the binding pockets for Gly-Leu-Met-NH₂ appear more restrictive. Consequently, five residues in the peptide are necessary for the high binding affinity to the antibody, the C-terminal tripeptide determining the binding specificity. These data, which appear to contradict those previously published, illustrate the limits of conclusions drawn from studies generally carried out using exclusively Ala-substituted peptides. In addition, the present results indicate that the topography of the binding site of this monoclonal antibody differs from that of the specific substance P neurokinin-1 receptor, in agreement with the differences observed in the fine specificities of these two substance P binding macromolecules. © 1996 John Wiley & Sons, Inc.     

Retrograde Effect of Muscle on Forms of Acetylcholinesterase in Peripheral Nerves

In the peripheral nerves of birds and mammals, acetylcholinesterase (AChE) exists in four main molecular forms (G1, G2, G4, and A12). The two heaviest forms (G4 and A12) are carried by rapid axoplasmic transport, whereas the two lightest forms (G1 and G2) are probably much more slowly transported. Here we report that nerves innervating fast-twitch (F nerves) and slow-twitch (S nerves) muscles of the rabbit differ both in their AChE molecular form patterns and in their anterograde and retrograde axonal transport parameters. Since we had previously shown a selective regulation of this enzyme in fast and slow parts of rabbit semimembranosus muscle, we wondered whether the differences observed in the nerve could be affected by the twitch properties of muscle. The results reported here show that in F nerves that reinnervate slow-twitch muscles, both the AChE molecular form patterns and axonal transport parameters turn into those of the S nerve. These data suggest the existence of a retrograde specific effect exerted by the muscles on their respective motoneurons.