The osteology of Shuvosaurus inexpectatus, a shuvosaurid pseudosuchian from the Upper Triassic Post Quarry, Dockum Group of Texas, USA.

A vast array of pseudosuchian body plans evolved during the diversification of the group in the Triassic Period, but few can compare to the toothless, long-necked, and bipedal shuvosaurids. Members of this clade possess theropod-like character states mapped on top of more plesiomorphic pseudosuchian character states, complicating our understanding of the evolutionary history of the skeleton. One taxon in this clade, Shuvosaurus inexpectatus has been assigned to various theropod dinosaur groups based on a partial skull and referred material and its postcranium was assigned to a different taxon in Pseudosuchia. After the discovery of a skeleton of a shuvosaurid with a Shuvosaurus-like skull and a pseudosuchian postcranial skeleton, it became clear Shuvosaurus inexpectatus was a pseudosuchian. Nevertheless, a number of questions have arisen about what skeletal elements belonged to Shuvosaurus inexpectatus, the identification of skull bones, and the resulting implication for pseudosuchian evolution. Here, we detail the anatomy of the skeleton Shuvosaurus inexpectatus through a critical lens, parse out the bones that belong to the taxon or those that clearly do not or may not belong to the taxon, rediagnose the taxon based on these revisions, and compare the taxon to other archosaurs. We find that Shuvosaurus inexpectatus possesses similar anatomy to other shuvosaurids but parts of the skeleton of the taxon clarifies the anatomy of the group given that they are preserved in Shuvosaurus inexpectatus but not in others. Shuvosaurus inexpectatus is represented by at least 14 individuals from the West Texas Post Quarry (Adamanian holochronozone) and all Shuvosaurus inexpectatus skeletal material from the locality pertains to skeletally immature individuals. All of the skeletons are missing most of the neural arches, ribs, and most of the forelimb. We only recognize Shuvosaurus inexpectatus from the Post Quarry and all other material assigned to the taxon previously is better assigned to the broader group Shuvosauridae.

Osteology of the sauropodomorph dinosaur Jaklapallisaurus asymmetricus from the Late Triassic of central India.

The Gondwana formations exposed in the Pranhita-Godavari Valley of central India include Middle Triassic to Lower Jurassic continental deposits that provide essential information about the tetrapod assemblages of that time, documenting some of the oldest known dinosaurs and the first faunas numerically dominated by this group. The Upper Maleri Formation of the Pranhita-Godavari Basin preserves an early-middle Norian dinosaur assemblage that provides information about the early evolutionary history of this group in central-south Gondwana. This assemblage comprises sauropodomorph dinosaurs and an herrerasaurian, including two nominal species. Here, we describe in detail the anatomy of one of those early dinosaurs, the bagualosaurian sauropodomorph Jaklapallisaurus asymmetricus. The new anatomical information is used to investigate the position of the species in an updated quantitative phylogenetic analysis focused on early sauropodomorphs. The analysis recovered Jaklapallisaurus asymmetricus as a member of Unaysauridae, at the base of Plateosauria, together with Macrocollum itaquii and Unaysaurus tolentinoi from the early Norian of southern Brazil. This phylogenetic result indicates that the dispersal of early plateosaurian sauropodomorphs between the Southern Hemisphere and what nowadays is Europe would have occurred shortly after Ischigualastian times because of the extension of their ghost lineage. Thus, the presence of early plateosaurians in the early Norian of South America and India reduces a previously inferred diachrony between the biogeographic dispersals of theropods and sauropodomorphs during post-Ischigualastian times.

Cranial anatomy of Libognathus sheddi Small, 1997 (Parareptilia, Procolophonidae) from the Upper Triassic Dockum Group of West Texas, USA.

Libognathus sheddi, a leptopleuronine procolophonid from the Upper Triassic Cooper Canyon Formation, Dockum Group, West Texas, was based on an isolated left dentary and partial coronoid. New material referable to Libognathus sheddi, from the Cooper Canyon Formation, provides new information on the cranial anatomy. This new cranial material includes the antorbital portion of a skull, a left maxilla and premaxilla, quadratojugals, and dentaries, including intact tooth rows in the upper and lower jaws. Libognathus shows autapomorphies including; dentary deep with ventral margin oblique to tooth row immediately from the symphysis at ≥23°; anterior projecting coronoid contacting the lingual surface of the dentary underlying the last two dentary teeth; reduced contact between the lacrimal and the nasal; suborbital foramen formed by the maxilla and ectopterygoid, excluding the palatine; a posterior supralabial foramen shared by the maxilla and jugal; a Y-shaped antorbital pillar formed by the palatine, and massive orbitonasale and facial foramina (shared with unnamed southwest USA leptopleuronines). Phylogenetic analysis indicates that Libognathus is a highly derived leptopleuronine procolophonid, closely related to Hypsognathus fenneri and other southwest USA Revueltian leptopleuronines, which fall out as sister taxa to Hypsognathus, a relationship supported by a maxillary dentition restricted anterior to the orbital margin, a possibly synapomorphic orbitonasale septum in the form of an "antorbital pillar" created by the palatine, an anteroventral process of the jugal, and the presence of a small diastema between the first dentary tooth and the more posterior dentition. Libognathus exhibits a possible ankylosed protothecodont tooth implantation with frequent replacement, differing from some other proposed procolophonid implantation and replacement models. Chinle Formation and Dockum Group leptopleuronines are restricted to the Revueltian teilzone/holochronozone, making them possible Revueltian index taxa.

The Coevolution of Biomolecules and Prebiotic Information Systems in the Origin of Life: A Visualization Model for Assembling the First Gene.

Prebiotic information systems exist in three forms: analog, hybrid, and digital. The Analog Information System (AIS), manifested early in abiogenesis, was expressed in the chiral selection, nucleotide formation, self-assembly, polymerization, encapsulation of polymers, and division of protocells. It created noncoding RNAs by polymerizing nucleotides that gave rise to the Hybrid Information System (HIS). The HIS employed different species of noncoding RNAs, such as ribozymes, pre-tRNA and tRNA, ribosomes, and functional enzymes, including bridge peptides, pre-aaRS, and aaRS (aminoacyl-tRNA synthetase). Some of these hybrid components build the translation machinery step-by-step. The HIS ushered in the Digital Information System (DIS), where tRNA molecules become molecular architects for designing mRNAs step-by-step, employing their two distinct genetic codes. First, they created codons of mRNA by the base pair interaction (anticodon-codon mapping). Secondly, each charged tRNA transferred its amino acid information to the corresponding codon (codon-amino acid mapping), facilitated by an aaRS enzyme. With the advent of encoded mRNA molecules, the first genes emerged before DNA. With the genetic memory residing in the digital sequences of mRNA, a mapping mechanism was developed between each codon and its cognate amino acid. As more and more codons 'remembered' their respective amino acids, this mapping system developed the genetic code in their memory bank. We compared three kinds of biological information systems with similar types of human-made computer systems.

A remarkable group of thick-headed Triassic Period archosauromorphs with a wide, possibly Pangean distribution.

The radiation of archosauromorph reptiles in the Triassic Period produced an unprecedented collection of diverse and disparate forms with a mix of varied ecologies and body sizes. Some of these forms were completely unique to the Triassic, whereas others were converged on by later members of Archosauromorpha. One of the most striking examples of this is with Triopticus primus, the early dome-headed form later mimicked by pachycephalosaurid dinosaurs. Here we fully describe the cranial anatomy of Triopticus primus, but also recognize a second dome-headed form from a Upper Triassic deposit in present-day India. The new taxon, Kranosaura kuttyi gen. et sp. nov., is likely the sister taxon of Triopticus primus based on the presence of a greatly expanded skull roof with a deep dorsal opening (possibly the pineal opening) through the dome, similar cranial sculpturing, and a skull table that is expanded more posterior than the posterior extent of the basioccipital. However, the dome of Kranosaura kuttyi gen. et sp. nov. extends anterodorsally, unlike that of any other archosauromorph. Histological sections and computed tomographic reconstructions through the skull of Kranosaura kuttyi gen. et sp. nov. further reveal the uniqueness of the dome of these early archosauromorphs. Moreover, our integrated analysis further demonstrates that there are many ways to create a dome in Amniota. The presence of 'dome-headed' archosauromorphs at two localities on the western and eastern portions of Pangea suggests that these archosauromorphs were widespread and are likely part of more assemblages than currently recognized.

The Origin of Prebiotic Information System in the Peptide/RNA World: A Simulation Model of the Evolution of Translation and the Genetic Code.

Information is the currency of life, but the origin of prebiotic information remains a mystery. We propose transitional pathways from the cosmic building blocks of life to the complex prebiotic organic chemistry that led to the origin of information systems. The prebiotic information system, specifically the genetic code, is segregated, linear, and digital, and it appeared before the emergence of DNA. In the peptide/RNA world, lipid membranes randomly encapsulated amino acids, RNA, and peptide molecules, which are drawn from the prebiotic soup, to initiate a molecular symbiosis inside the protocells. This endosymbiosis led to the hierarchical emergence of several requisite components of the translation machine: transfer RNAs (tRNAs), aminoacyl-tRNA synthetase (aaRS), messenger RNAs (mRNAs), ribosomes, and various enzymes. When assembled in the right order, the translation machine created proteins, a process that transferred information from mRNAs to assemble amino acids into polypeptide chains. This was the beginning of the prebiotic information age. The origin of the genetic code is enigmatic; herein, we propose an evolutionary explanation: the demand for a wide range of protein enzymes over peptides in the prebiotic reactions was the main selective pressure for the origin of information-directed protein synthesis. The molecular basis of the genetic code manifests itself in the interaction of aaRS and their cognate tRNAs. In the beginning, aminoacylated ribozymes used amino acids as a cofactor with the help of bridge peptides as a process for selection between amino acids and their cognate codons/anticodons. This process selects amino acids and RNA species for the next steps. The ribozymes would give rise to pre-tRNA and the bridge peptides to pre-aaRS. Later, variants would appear and evolution would produce different but specific aaRS-tRNA-amino acid combinations. Pre-tRNA designed and built pre-mRNA for the storage of information regarding its cognate amino acid. Each pre-mRNA strand became the storage device for the genetic information that encoded the amino acid sequences in triplet nucleotides. As information appeared in the digital languages of the codon within pre-mRNA and mRNA, and the genetic code for protein synthesis evolved, the prebiotic chemistry then became more organized and directional with the emergence of the translation and genetic code. The genetic code developed in three stages that are coincident with the refinement of the translation machines: the GNC code that was developed by the pre-tRNA/pre-aaRS /pre-mRNA machine, SNS code by the tRNA/aaRS/mRNA machine, and finally the universal genetic code by the tRNA/aaRS/mRNA/ribosome machine. We suggest the coevolution of translation machines and the genetic code. The emergence of the translation machines was the beginning of the Darwinian evolution, an interplay between information and its supporting structure. Our hypothesis provides the logical and incremental steps for the origin of the programmed protein synthesis. In order to better understand the prebiotic information system, we converted letter codons into numerical codons in the Universal Genetic Code Table. We have developed a software, called CATI (Codon-Amino Acid-Translator-Imitator), to translate randomly chosen numerical codons into corresponding amino acids and vice versa. This conversion has granted us insight into how the genetic code might have evolved in the peptide/RNA world. There is great potential in the application of numerical codons to bioinformatics, such as barcoding, DNA mining, or DNA fingerprinting. We constructed the likely biochemical pathways for the origin of translation and the genetic code using the Model-View-Controller (MVC) software framework, and the translation machinery step-by-step. While using AnyLogic software, we were able to simulate and visualize the entire evolution of the translation machines, amino acids, and the genetic code.

A new sauropodiform dinosaur with a 'sauropodan' skull from the Lower Jurassic Lufeng Formation of Yunnan Province, China.

The Early Jurassic Lufeng Formation of Yunnan Province in southwestern China is one of the best fossil localities in the world for understanding the early radiation of sauropodomorph dinosaurs. It has yielded a rich assemblage of complete and three-dimensionally preserved skeletons of herbivorous dinosaurs that provide crucial morphological information for systematic and evolutionary studies. Here we describe a new taxon, Yizhousaurus sunae gen. et sp. nov., represented by a nearly complete skeleton with an exquisitely preserved skull and mandible. Yizhousaurus is distinguished from other non-sauropodan sauropodomorphs by a unique combination of plesiomorphic and apomorphic features, which increases our understanding of the anatomical variation on the relatively conservative 'prosauropod' cranial plan. Phylogenetic analysis resolves Yizhousaurus as a sauropodiform, showcasing a mosaic character suite combining plesiomorphic states in the postcranial skeleton with some more 'sauropodan'-like features in the skull. Furthermore, Yizhousaurus is placed closer to the base of Sauropoda than other non-sauropodan sauropodomorphs currently known from the Lufeng Formation, adding another taxon to enrich the Lower Jurassic Lufeng dinosaur fauna.

Vegaviidae, a new clade of southern diving birds that survived the K/T boundary.

The fossil record of Late Cretaceous-Paleogene modern birds in the Southern Hemisphere includes the Maastrichtian Neogaeornis wetzeli from Chile, Polarornis gregorii and Vegavis iaai from Antarctica, and Australornis lovei from the Paleogene of New Zealand. The recent finding of a new and nearly complete Vegavis skeleton constitutes the most informative source for anatomical comparisons among Australornis, Polarornis, and Vegavis. The present contribution includes, for the first time, Vegavis, Polarornis, and Australornis in a comprehensive phylogenetic analysis. This analysis resulted in the recognition of these taxa as a clade of basal Anseriformes that we call Vegaviidae. Vegaviids share a combination of characters related to diving adaptations, including compact and thickened cortex of hindlimb bones, femur with anteroposteriorly compressed and bowed shaft, deep and wide popliteal fossa delimited by a medial ridge, tibiotarsus showing notably proximally expanded cnemial crests, expanded fibular crest, anteroposterior compression of the tibial shaft, and a tarsometatarsus with a strong transverse compression of the shaft. Isolated bones coming from the Cretaceous and Paleogene of South America, Antarctica, and New Zealand are also referred to here to Vegaviidae and support the view that these basal anseriforms were abundant and diverse at high southern latitudes. Moreover, vegaviids represent the first avian lineage to have definitely crossed the K-Pg boundary, supporting the idea that some avian clades were not affected by the end Mesozoic mass extinction event, countering previous interpretations. Recognition of Vegaviidae indicates that modern birds were diversified in southern continents by the Cretaceous and reinforces the hypothesis indicating the important role of Gondwana for the evolutionary history of Anseriformes and Neornithes as a whole.

Fossil evidence of the avian vocal organ from the Mesozoic.

From complex songs to simple honks, birds produce sounds using a unique vocal organ called the syrinx. Located close to the heart at the tracheobronchial junction, vocal folds or membranes attached to modified mineralized rings vibrate to produce sound. Syringeal components were not thought to commonly enter the fossil record, and the few reported fossilized parts of the syrinx are geologically young (from the Pleistocene and Holocene (approximately 2.5 million years ago to the present)). The only known older syrinx is an Eocene specimen that was not described or illustrated. Data on the relationship between soft tissue structures and syringeal three-dimensional geometry are also exceptionally limited. Here we describe the first remains, to our knowledge, of a fossil syrinx from the Mesozoic Era, which are preserved in three dimensions in a specimen from the Late Cretaceous (approximately 66 to 69 million years ago) of Antarctica. With both cranial and postcranial remains, the new Vegavis iaai specimen is the most complete to be recovered from a part of the radiation of living birds (Aves). Enhanced-contrast X-ray computed tomography (CT) of syrinx structure in twelve extant non-passerine birds, as well as CT imaging of the Vegavis and Eocene syrinxes, informs both the reconstruction of ancestral states in birds and properties of the vocal organ in the extinct species. Fused rings in Vegavis form a well-mineralized pessulus, a derived neognath bird feature, proposed to anchor enlarged vocal folds or labia. Left-right bronchial asymmetry, as seen in Vegavis, is only known in extant birds with two sets of vocal fold sound sources. The new data show the fossilization potential of the avian vocal organ and beg the question why these remains have not been found in other dinosaurs. The lack of other Mesozoic tracheobronchial remains, and the poorly mineralized condition in archosaurian taxa without a syrinx, may indicate that a complex syrinx was a late arising feature in the evolution of birds, well after the origin of flight and respiratory innovations.

A symbiotic view of the origin of life at hydrothermal impact crater-lakes.

Submarine hydrothermal vents are generally considered as the likely habitats for the origin and evolution of early life on Earth. The theory suffers from the 'concentration problem' of cosmic and terrestrial biomolecules because of the vastness of the Eoarchean global ocean. An attractive alternative site would be highly sequestered, small, hydrothermal crater-lakes that might have cradled life on early Earth. A new symbiotic model for the origin of life at hydrothermal crater-lakes is proposed here. Meteoritic impacts on the Eoarchean crust at the tail end of the Heavy Bombardment period might have played important roles in the origin of life. Impacts and collisions that created hydrothermal crater lakes on the Eoarchean crust inadvertently became the perfect crucibles for prebiotic chemistry with building blocks of life, which ultimately led to the first organisms by prebiotic synthesis. In this scenario, life arose through four hierarchical stages of increasing molecular complexity in multiple niches of crater basins. In the cosmic stage (≥4.6 Ga), the building blocks of life had their beginnings in the interstellar space during the explosion of a nearby star. Both comets and carbonaceous chondrites delivered building blocks of life and ice to early Earth, which were accumulated in hydrothermal impact crater-lakes. In the geologic stage (∼4 Ga), crater basins contained an assortment of cosmic and terrestrial organic compounds, powered by hydrothermal, solar, tidal, and chemical energies, which drove the prebiotic synthesis. At the water surface, self-assembled primitive lipid membranes floated as a thick oil slick. Archean Greenstone belts in Greenland, Australia, and South Africa possibly represent the relics of these Archean craters, where the oldest fossils of thermophilic life (∼3.5 Ga) have been detected. In the chemical stage, monomers such as nucleotides and amino acids were selected from random assemblies of the prebiotic soup; they were polymerized at pores of mineral surfaces with the coevolution of RNA and protein molecules to form the 'RNA/protein world'. Lipid membranes randomly encapsulated these RNA and protein molecules to initiate a molecular symbiosis in a 'RNA/protein/lipid world' that led to hierarchical emergence of several cell components: plasma membranes, ribosomes, coding RNA and proteins, DNA, and finally protocells with a primitive genetic code. In the biological stage, the emergence of the first cells capable of reproduction, heredity, variation, and Darwinian evolution is the key breakthrough in the origin of life. RNA virus and prions may represent the evolutionary relics of the RNA/protein world that survived as parasites for billions of years. Although the proposed endosymbiotic model is speculative it has intrinsic heuristic value. Future experiments on encapsulated RNA virus and prions have the potential to create a synthetic cell that may confirm a coherent narrative of this hierarchical evolutionary sequence.

In search of next generation antimalarials.

Compounds 7-10 displayed potency without any apparent toxicity, in animal models of both relapsing and non-relapsing forms of malaria offering hope of a single molecule that can cure both relapsing and non relapsing forms of malaria.

Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 receptor antagonists.

Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 (5-HT6) receptor antagonists have been disclosed. One potent member from the lactam series, racemic compound 14 (Ki of 2.6 nM in binding assay, IC50 of 15 nM in functional cAMP antagonism assay) was separated into corresponding enantiomers that displayed the effect of chirality on binding potency (Ki of 1.6 nM and 3000 nM, respectively). The potent enantiomer displayed an IC50 of 8 nM in cAMP antagonism assay, selectivity against a number of family members as well as brain permeability in rats after 6h post oral administration.

In search of potent 5-HT6 receptor inverse agonists.

A series of non-sulfonamide/non-sulfone derived potent 5-HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki  = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post-oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating the influence of chirality on potency.

1-Thia-4,7-diaza-spiro[4.4]nonane-3,6-dione: a structural motif for 5-hydroxytryptamine 6 receptor antagonism.

A series of potent 5-hydroxytryptamine 6 (5-HT6) receptor antagonists based on 1-thia-4,7-diaza-spiro[4.4]nonane-3,6-dione motif has been disclosed. Enantiomers of potent racemate compound 8a (K(i) = 26 nM) displayed difference in activity (K(i) of 15 nM versus 855 nM) signaling the influence of the stereochemistry of the chiral center on potency. In addition, the potent enantiomer displayed significant selectivity in biological activities over several related family members.

Synthesis and activity of proteasome inhibitors.

Among its various catalytic activities, "chymotrypsin-like" activity of proteasome, a large multicatalytic proteinase complex has emerged as the focus of drug discovery efforts in cancer therapy. Herein, we report results from our investigation on a series of peptidomimetic inhibitors.

Serendipitous discovery of a prodrug of a PARP-1 inhibitor.

During SAR development of previously reported pyrrolocarbazole 1, a potent PARP-1 inhibitor, compound 14, was discovered serendipitously to be a prodrug of compound 1.

Aryl-heteroaryl derivatives as novel wake-promoting agents.

In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.

From an atypical wake-promoting agent to potent histamine-3 receptor inverse agonists.

Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).

Wake-promoting agents: search for next generation modafinil: part IV.

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of diphenyl ether derived wakefulness enhancing agents (in rat) was developed. From this work, racemic compound 16 was separated into its chiral enantiomers to profile them individually.

Wake promoting agents: search for next generation modafinil, lessons learned: part III.

In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).