Ossification patterns of the carpus and tarsus in salamanders and impacts of preaxial dominance on the fin-to-limb transition.

Early limb skeletogenesis in salamanders is characterized by preaxial elements, digits I and II forming earlier than their postaxial counterparts (digits III to V), a phenomenon known as preaxial dominance, whereas in amniotes and anurans, these developmental sequences are reversed. This pattern characterizes the late skeletogenesis of digits and zeugopodium of anamniote tetrapods but remains unknown in carpals/tarsals. To correct this gap in knowledge, we investigate the ossification patterns of the carpals/tarsals in six salamander families/clades based on micro-computed tomography scans. We found that preaxial dominance is seen in the distal carpals/tarsals of several salamander clades and diverse early tetrapods, such as temnospondyls and amniotes. This distribution suggests that preaxial dominance is a primitive developmental pattern in tetrapods. Our results demonstrate that the distal carpals/tarsals are developmentally and evolutionarily independent in the autopodium, and preaxial dominance facilitates stabilization of the number of distal carpals/tarsals during fin-to-limb transition and digit reduction in early tetrapods.

Palatal morphology predicts the paleobiology of early salamanders.

Ecological preferences and life history strategies have enormous impacts on the evolution and phenotypic diversity of salamanders, but the yet established reliable ecological indicators from bony skeletons hinder investigations into the paleobiology of early salamanders. Here, we statistically demonstrate by using time-calibrated cladograms and geometric morphometric analysis on 71 specimens in 36 species, that both the shape of the palate and many non-shape covariates particularly associated with vomerine teeth are ecologically informative in early stem- and basal crown-group salamanders. Disparity patterns within the morphospace of the palate in ecological preferences, life history strategies, and taxonomic affiliations were analyzed in detail, and evolutionary rates and ancestral states of the palate were reconstructed. Our results show that the palate is heavily impacted by convergence constrained by feeding mechanisms and also exhibits clear stepwise evolutionary patterns with alternative phenotypic configurations to cope with similar functional demand. Salamanders are diversified ecologically before the Middle Jurassic and achieved all their present ecological preferences in the Early Cretaceous. Our results reveal that the last common ancestor of all salamanders share with other modern amphibians a unified biphasic ecological preference, and metamorphosis is significant in the expansion of ecomorphospace of the palate in early salamanders.

Middle Jurassic stem hynobiids from China shed light on the evolution of basal salamanders.

The Hynobiidae are an early-diverging clade of crown-group salamanders (urodeles) with an important bearing on the evolution of urodeles. Paleobiology and early-branching patterns of the Hynobiidae remain unclear owing to a poorly documented fossil record. We reported a newly referred specimen to the stem hynobiid, originally named as "Liaoxitriton daohugouensis," but here as Neimengtriton daohugouensis comb. nov., and predates the previously estimated origination time of Hynobiidae for at least 8 Myr. We interpret N. daohugouensis as semiaquatic at the adult stage, a previously unknown paleoecological preference among Mesozoic salamanders. Phenotypic variations of N. daohugouensis enlighten an unrecognized association between caudosacral vertebrae and fertilization modes in the early evolution of urodeles. Our cladistic analyses based on morphological characters not only recognize several stem hynobiids and establish Panhynobia nomen cladinovum for the total-group hynobiids but also shed light on the sequential evolution of morphological features in this primitive urodele clade.

Interactive Effects of Glucocorticoids and Cytochrome P450 Polymorphisms on the Plasma Trough Concentrations of Voriconazole.

Aims: To explore the interactive influence of glucocorticoids and cytochrome P450 (CYP450) polymorphisms on voriconazole (VRC) plasma trough concentrations (Cmin) and provide a reliable basis for reasonable application of VRC. Methods: A total of 918 VRC Cmin from 231 patients was collected and quantified using high-performance liquid chromatography in this study. The genotypes of CYP2C19, CYP3A4, and CYP3A5 were detected by DNA sequencing assay. The effects of different genotypes and the coadministration of glucocorticoids on VRC Cmin were investigated. Furthermore, the interactive effects of glucocorticoids with CYP450s on VRC Cmin were also analyzed. Results: The median Cmin of oral administration was lower than that of intravenous administration (1.51 vs. 4.0 mg l-1). Coadministration of glucocorticoids (including dexamethasone, prednisone, prednisolone, and methylprednisolone) reduced the VRC Cmin/dose, respectively, among which dexamethasone make the median of the VRC Cmin/dose ratio lower. As a result, when VRC was coadministrated with glucocorticoids, the proportion of VRC Cmin/dose in the subtherapeutic window was increased. Different CYP450 genotypes have different effects on the Cmin/dose of VRC. Mutations of CYP2C19*2 and *3 increased Cmin/dose of VRC, while CYP2C19*17 and CYP3A4 rs4646437 polymorphisms decreased Cmin/dose of VRC. The mutation of CYP3A5 has no significant effect. Furthermore, CYP2C19*17 mutants could strengthen the effects of glucocorticoids and decrease VRC Cmin/dose to a larger extent. Conclusion: Our study revealed that glucocorticoids reduced the Cmin/dose levels of VRC and different SNPs of CYP450 have different effects on the Cmin/dose ratio of VRC. Glucocorticoids and CYP2C19*17 mutants had a synergistic effect on reducing VRC Cmin/dose. The present results suggested that when VRC is combined with glucocorticoids, we should pay more attention to the clinical efficacy of VRC, especially when CYP2C19*17 mutants exist.

Comparative osteology of the hynobiid complex Liua-Protohynobius-Pseudohynobius (Amphibia, Urodela): â . Cranial anatomy of Pseudohynobius.

Hynobiidae are a clade of salamanders that diverged early within the crown radiation and that retain a considerable number of features plesiomorphic for the group. Their evolutionary history is informed by a fossil record that extends to the Middle Jurassic Bathonian time. Our understanding of the evolution within the total group of Hynobiidae has benefited considerably from recent discoveries of stem hynobiids but is constrained by inadequate anatomical knowledge of some extant forms. Pseudohynobius is a derived hynobiid clade consisting of five to seven extant species living endemic to southwestern China. Although this clade has been recognized for over 37 years, osteological details of these extant hynobiids remain elusive, which undoubtedly has contributed to taxonomic controversies over the hynobiid complex Liua-Protohynobius-Pseudohynobius. Here we provide a bone-by-bone study of the cranium in the five extant species of Pseudohynobius (Ps. flavomaculatus, Ps. guizhouensis, Ps. jinfo, Ps. kuankuoshuiensis and Ps. shuichengensis) based on x-ray computer tomography data for 18 specimens. Our results indicate that the cranium in each of these species has a combination of differences in morphology, proportions and articulation patterns in both dermal and endochondral bones. Our study establishes a range of intraspecific differences that will serve as organizing hypotheses for future studies as more extensive collections of these species become available. Morphological features in the cranium for terrestrial ecological adaptation in Hynobiidae are summarized. Based on the results, we also discuss the evolution and development of several potential synapomorphies of Hynobiidae, including features of the orbitosphenoid and articular.

Osteology of Batrachuperus yenyuanensis (Urodela, Hynobiidae), a high-altitude mountain stream salamander from western China.

Batrachuperus yenyuanensis, commonly known as Yenyuan Stream Salamander, is a hynobiid species inhabiting high-altitude (2440-4025 m above sea level) mountain stream and pond environments along the eastern fringe of the Qinghai-Tibetan Plateau in western Sichuan Province, China. Although the species has been known for almost 70 years since its initial discovery in 1950, a thorough osteological description has never been provided. Our study provides a detailed account of the bony anatomy of this species, based on micro computed tomography scanning of multiple specimens collected from the type locality Shuangertang at Bailinshan, Yanyuan County, and several other localities in Sichuan Province. Our revised species diagnosis utilizes both bony and soft anatomical features. Comparative study of the specimens from the type locality in Yanyuan area with those from the nearby Xichang and Mianning areas confirms that they all pertain to Batrachuperus yenyuanensis, thereby removing doubt on the occurrence of the species in the latter areas. With this confirmation, the distribution of the species is extended from the type locality northwards some 180 km to the Mianning area, on both the west and east sides of the Yalong River, which is a major tributary of the upper Yangtze River. This distribution pattern indicates that the biogeographic origin and historical evolution of the species are closely associated with the orogeny of the Hengduan Mountains and formation of the Yalong River. Given the basalmost position of Batrachuperus yenyuanensis in relation to other congeneric species based on molecular studies, however, early expansion of the species distribution by dispersal is expected following the origin of the genus in early-middle Miocene in western Sichuan Province. Thus, the species may well have achieved its current distribution in western Sichuan before the drastic uplift of the Qinghai-Tibetan Plateau in Pliocene.

Elaborate plumage patterning in a Cretaceous bird.

Integumentary patterns and colors can differentiate species, sexes, and life changes and can inform on habitat and ecology. However, they are rarely preserved in the fossil record. Here, we report on an extremely well-preserved specimen of the Cretaceous bird Confuciusornis with unprecedented complexity, including small spots on the wings, crest, and throat. Morphological and chemical evidence suggest that these patterns are produced by melanin, but unusual preservation prevents assignment of specific colors. Based on comparisons with extant birds, these patterns were likely used for camouflage, although other functions including sexual signaling cannot be ruled out. Our data show that even more elaborate plumage patterns than the spangles in Anchiornis and stripes in Sinosauropteryx were present at a relatively early stage of avian evolution, showing the significance of coloration and patterning to feather evolution.

Aberrant histone modifications of global histone and MCP-1 promoter in CD14+ monocytes from patients with coronary artery disease.

OBJECTIVES: To investigate whether there are aberrant acetylation modifications in global histone and monocyte chemoattractant protein-1 (MCP-1) promoter in monocytes from patients with coronary artery disease (CAD) and demonstrate the potential mechanisms. METHODS: CD14+ monocytes were isolated from 13 patients with CAD and 18 confirmed non-CAD controls using magnetic beads. Global histone H3/H4 acetylation and H3K4/H3K27 tri-methylation levels were measured with enzyme-linked immunosorbent assay. Quantitative real time-PCR was performed to detect the mRNA expression levels of MCP-1 and enzymes involved in histone modification processes. Histone modification levels in MCP-1 promoter were assessed by ChIP-qPCR assay. RESULTS: Our results showed a markedly lower global histone H3 acetylation level in monocytes from CAD patients. Global H3K27 tri-methylation level was significantly increased in monocytes from CAD patients. Furthermore, the mRNA expression levels of epigenetic modification enzymes HDAC3, SIRT1, P300, JMJD3 and SUV39H1 were decreased significantly in monocytes from CAD patients, while HDAC7 mRNA expression level was markedly increased. MCP-1 mRNA expression level was increased histone H3/H4 acetylation levels in MCP-1 promoter were markedly increased in monocytes of CAD patients. CONCLUSION: Aberrant histone modifications, including acetylation and tri-methylation, were found both in global histone and specific MCP-1 gene locos in monocytes from patients with CAD. Aberrant epigenetic modification enzymes expressions may be the regulatory mechanism responsible for aberrant histone modifications.

Osteology of Batrachuperus londongensis (Urodela, Hynobiidae): study of bony anatomy of a facultatively neotenic salamander from Mount Emei, Sichuan Province, China.

The Longdong Stream Salamander Batrachuperus londongensis, living in a mountain stream environment at Mt. Emei in Sichuan Province, China, represents a rare species that is facultatively neotenic in the family Hynobiidae. Although the species has been known to science for some 40 years since its initial discovery in the late 1970s, anatomical details of its osteology remain poorly understood and developmental information is still lacking for the species. This study (1) provides a detailed osteological account of B. londongensis based on micro-CT scanning and clearing and staining of multiple specimens from the type locality; (2) provides a discussion of intraspecific variation related to life-history differences; and (3) presents a discussion on limb features related to morphological evolution of limb patterns correlative with ecological adaptation to mountain stream environments. Osteological comparisons with congeneric species has led to recognition of several diagnostic features that are unique to B. londongensis, including: vomers widely separated from one another, lacking a midline contact; presence of uncommon perichondral ossification of the ascending process of the palatoquadrate as part of the suspensorium; and presence of a prominent posterodorsal process of the scapular blade, which serves as a ligamentous insertion of the levator muscle of the scapula. In addition, some but not all neotenic individuals retain the palatine as a discrete element, indicative of its delayed absorption after sexual maturity. Postmetamorphic and neotenic individuals are strikingly different in the complexity of hyobranchial structures. Neotenes display a high degree of ossification of hyobranchial elements, tend to increase ossification of both hypobranchial I and ceratobranchial I during aging, and retain fully ossified ceratobranchial III and IV; in contrast, these elements remain entirely cartilaginous or are totally lost by resorption in postmetamorphic individuals. In addition, all postmetamorphic forms display an inverted "T"-shaped basibranchial II, whereas neotenes show transformation from a "fork"-shaped to the "T"-shaped configuration after sexual maturity. B. londongensis displays a mosaic of apomorphic and plesiomorphic states in its limb ossifications: presence of a single centrale element in both the manus and pes is a derived condition in Hynobiidae and other families as well, whereas retention of a postminimus in the pes is obviously plesiomorphic within Urodela. Reduction in number of digits from five to four in the pes and possession of a cornified sheath covering the terminal phalanges are also derived features shared with some but not all mountain stream salamanders that are adapted to a similar type of environment.

Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4+ T cells of systemic lupus erythematosus.

DNA hypomethylation plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus CD4+ T cells. Our results showed that BDH2 expression was decreased, intracellular iron was increased, global DNA hydroxymethylation level was elevated, while methylation level was reduced in lupus CD4+ T cells compared with healthy controls. The decreased BDH2 contributed to DNA hyper-hydroxymethylation and hypomethylation via increasing intracellular iron in CD4+ T cells, which led to overexpression of immune related genes. Moreover, we showed that BDH2 was the target gene of miR-21. miR-21 promoted DNA demethylation in CD4+ T cells through inhibiting BDH2 expression. Our data demonstrated that the dysregulation of iron homeostasis in CD4+ T cells induced by BDH2 deficiency contributes to DNA demethylation and self-reactive T cells in SLE.

Earliest filter-feeding pterosaur from the Jurassic of China and ecological evolution of Pterodactyloidea.

Pterosaurs were a unique clade of flying reptiles that were contemporaries of dinosaurs in Mesozoic ecosystems. The Pterodactyloidea as the most species-diverse group of pterosaurs dominated the sky during Cretaceous time, but earlier phases of their evolution remain poorly known. Here, we describe a 160 Ma filter-feeding pterosaur from western Liaoning, China, representing the geologically oldest record of the Ctenochasmatidae, a group of exclusive filter feeders characterized by an elongated snout and numerous fine teeth. The new pterosaur took the lead of a major ecological transition in pterosaur evolution from fish-catching to filter-feeding adaptation, prior to the Tithonian (145-152 Ma) diversification of the Ctenochasmatidae. Our research shows that the rise of ctenochasmatid pterosaurs was followed by the burst of eco-morphological divergence of other pterodactyloid clades, which involved a wide range of feeding adaptations that considerably altered the terrestrial ecosystems of the Cretaceous world.

Epigenetic regulation in monocyte/macrophage: A key player during atherosclerosis.

Atherosclerosis is a chronic inflammatory disease. Recently, a growing body of evidence emphasizes that the monocyte and macrophage differentiation and activation are key processes in the development of atherosclerosis. However, the regulatory mechanism that manipulates the function of monocyte and macrophage is still unclear. Recent years, epigenetic mechanisms have received a wide attention and bring us a new field of vision. More and more evidence shows that epigenetics weighs heavily in atherosclerosis by regulating the function and differentiation states of monocyte and macrophage. In this review, we illuminate the epigenetic regulation mechanisms in monocyte and macrophage and their contributions to inflammatory processes of atherosclerosis to provide new thoughts and find novel targets or biomarkers for atherosclerosis.

A new hynobiid-like salamander (Amphibia, Urodela) from Inner Mongolia, China, provides a rare case study of developmental features in an Early Cretaceous fossil urodele.

A new fossil salamander, Nuominerpeton aquilonaris (gen. et sp. nov.), is named and described based on specimens from the Lower Cretaceous Guanghua Formation of Inner Mongolia, China. The new discovery documents a far northern occurrence of Early Cretaceous salamanders in China, extending the geographic distribution for the Mesozoic fossil record of the group from the Jehol area (40th-45th parallel north) to near the 49th parallel north. The new salamander is characterized by having the orbitosphenoid semicircular in shape; coracoid plate of the scapulocoracoid greatly expanded with a convex ventral and posterior border; ossification of two centralia in carpus and tarsus; and first digit being about half the length of the second digit in both manus and pes. The new salamander appears to be closely related to hynobiids, although this inferred relationship awaits confirmation by research in progress by us on a morphological and molecular combined analysis of cryptobranchoid relationships. Comparison of adult with larval and postmetamorphic juvenile specimens provides insights into developmental patterns of cranial and postcranial skeletons in this fossil species, especially resorption of the palatine and anterior portions of the palatopterygoid in the palate and the coronoid in the mandible during metamorphosis, and postmetamorphic ossification of the mesopodium in both manus and pes. Thus, this study provides a rare case study of developmental features in a Mesozoic salamander.

A New Basal Salamandroid (Amphibia, Urodela) from the Late Jurassic of Qinglong, Hebei Province, China.

A new salamandroid salamander, Qinglongtriton gangouensis (gen. et sp. nov.), is named and described based on 46 fossil specimens of juveniles and adults collected from the Upper Jurassic (Oxfordian) Tiaojishan Formation cropping out in Hebei Province, China. The new salamander displays several ontogenetically and taxonomically significant features, most prominently the presence of a toothed palatine, toothed coronoid, and a unique pattern of the hyobranchium in adults. Comparative study of the new salamander with previously known fossil and extant salamandroids sheds new light on the early evolution of the Salamandroidea, the most species-diverse clade in the Urodela. Cladistic analysis places the new salamander as the sister taxon to Beiyanerpeton, and the two taxa together form the basalmost clade within the Salamandroidea. Along with recently reported Beiyanerpeton from the same geological formation in the neighboring Liaoning Province, the discovery of Qinglongtriton indicates that morphological disparity had been underway for the salamandroid clade by early Late Jurassic (Oxfordian) time.

Melanosome evolution indicates a key physiological shift within feathered dinosaurs.

Inference of colour patterning in extinct dinosaurs has been based on the relationship between the morphology of melanin-containing organelles (melanosomes) and colour in extant bird feathers. When this relationship evolved relative to the origin of feathers and other novel integumentary structures, such as hair and filamentous body covering in extinct archosaurs, has not been evaluated. Here we sample melanosomes from the integument of 181 extant amniote taxa and 13 lizard, turtle, dinosaur and pterosaur fossils from the Upper-Jurassic and Lower-Cretaceous of China. We find that in the lineage leading to birds, the observed increase in the diversity of melanosome morphologies appears abruptly, near the origin of pinnate feathers in maniraptoran dinosaurs. Similarly, mammals show an increased diversity of melanosome form compared to all ectothermic amniotes. In these two clades, mammals and maniraptoran dinosaurs including birds, melanosome form and colour are linked and colour reconstruction may be possible. By contrast, melanosomes in lizard, turtle and crocodilian skin, as well as the archosaurian filamentous body coverings (dinosaur 'protofeathers' and pterosaur 'pycnofibres'), show a limited diversity of form that is uncorrelated with colour in extant taxa. These patterns may be explained by convergent changes in the key melanocortin system of mammals and birds, which is known to affect pleiotropically both melanin-based colouration and energetic processes such as metabolic rate in vertebrates, and may therefore support a significant physiological shift in maniraptoran dinosaurs.

A new stem-neopterygian fish from the Middle Triassic of China shows the earliest over-water gliding strategy of the vertebrates.

Flying fishes are extraordinary aquatic vertebrates capable of gliding great distances over water by exploiting their enlarged pectoral fins and asymmetrical caudal fin. Some 50 species of extant flying fishes are classified in the Exocoetidae (Neopterygii: Teleostei), which have a fossil record no older than the Eocene. The Thoracopteridae is the only pre-Cenozoic group of non-teleosts that shows an array of features associated with the capability of over-water gliding. Until recently, however, the fossil record of the Thoracopteridae has been limited to the Upper Triassic of Austria and Italy. Here, we report the discovery of exceptionally well-preserved fossils of a new thoracopterid flying fish from the Middle Triassic of China, which represents the earliest evidence of an over-water gliding strategy in vertebrates. The results of a phylogenetic analysis resolve the Thoracopteridae as a stem-group of the Neopterygii that is more crown-ward than the Peltopleuriformes, yet more basal than the Luganoiiformes. As the first record of the Thoracopteride in Asia, this new discovery extends the geographical distribution of this group from the western to eastern rim of the Palaeotethys Ocean, providing new evidence to support the Triassic biological exchanges between Europe and southern China. Additionally, the Middle Triassic date of the new thoracopterid supports the hypothesis that the re-establishment of marine ecosystems after end-Permian mass extinction is more rapid than previously thought.

Reconstruction of Microraptor and the evolution of iridescent plumage.

Iridescent feather colors involved in displays of many extant birds are produced by nanoscale arrays of melanin-containing organelles (melanosomes). Data relevant to the evolution of these colors and the properties of melanosomes involved in their generation have been limited. A data set sampling variables of extant avian melanosomes reveals that those forming most iridescent arrays are distinctly narrow. Quantitative comparison of these data with melanosome imprints densely sampled from a previously unknown specimen of the Early Cretaceous feathered Microraptor predicts that its plumage was predominantly iridescent. The capacity for simple iridescent arrays is thus minimally inferred in paravian dinosaurs. This finding and estimation of Microraptor feathering consistent with an ornamental function for the tail suggest a centrality for signaling in early evolution of plumage and feather color.

Late Jurassic salamandroid from western Liaoning, China.

A Jurassic salamander, Beiyanerpeton jianpingensis (gen. et sp. nov.), from a recently found site in western Liaoning Province, China is the earliest known record of Salamandroidea. As a Late Jurassic record of the group, it extends the range of the clade by ~40 Ma. The Late Jurassic taxon is neotenic and represented by exceptionally preserved specimens, including fully articulated cranial and postcranial skeletons and bony gill structures close to the cheek region. The fossil beds, consisting of dark-brown volcanic ash shales of the Upper Jurassic Tiaojishan (Lanqi) Formation (Oxfordian), underlie trachyandesite rocks that have yielded a SHRIMP zircon U-Pb date of 157 ± 3 Ma. The fossiliferous beds are substantially older than the Jehol Group, including the Yixian Formation ((40)Ar/(39)Ar dates of 122-129 Ma), but slightly younger than the Middle Jurassic Daohugou horizon ((40)Ar/(39)Ar date of 164 ± 4 Ma). The early fossil taxon shares with extant salamandroids derived character states, including: separated nasals lacking a midline contact, angular fused to the prearticular in the lower jaw, and double-headed ribs on the presacral vertebrae. In contrast to extant salamandroids, however, the salamander shows a discrete and tooth-bearing palatine, and unequivocally nonpedicellate and monocuspid marginal teeth in large and presumably mature individuals. The finding provides insights into the evolution of key characters of salamanders, and also provides direct evidence supporting the hypothesis that the split between Cryptobranchoidea and Salamandroidea had taken placed before the Late Jurassic Oxfordian time. In this aspect, both paleontological and molecular data now come to agree.

Plumage color patterns of an extinct dinosaur.

For as long as dinosaurs have been known to exist, there has been speculation about their appearance. Fossil feathers can preserve the morphology of color-imparting melanosomes, which allow color patterns in feathered dinosaurs to be reconstructed. Here, we have mapped feather color patterns in a Late Jurassic basal paravian theropod dinosaur. Quantitative comparisons with melanosome shape and density in extant feathers indicate that the body was gray and dark and the face had rufous speckles. The crown was rufous, and the long limb feathers were white with distal black spangles. The evolution of melanin-based within-feather pigmentation patterns may coincide with that of elongate pennaceous feathers in the common ancestor of Maniraptora, before active powered flight. Feathers may thus have played a role in sexual selection or other communication.