The WNT7A G204S mutation is associated with both Al-Awadi–Raas Rothschild syndrome and Fuhrmann syndrome phenotypes

Two syndromes are known to be associated with WNT7A mutations: Al-Awadi–Raas-Rothschild syndrome (AARRS) and Fuhrmann syndrome. Woods et al. (2006) showed that there is complete and partial loss of WNT7A function in these two syndromes respectively. Therefore, both syndromes have similar clinical features but the phenotype in Fuhrmann syndrome is less severe. The G204S mutation was previously reported to result in AARRS phenotype in three Saudi families. In the current communication, we report on a different unrelated Saudi patient with the same mutation but the patient had Fuhrmann syndrome phenotype. We believe this case is important because it questions the presence of a phenotype–genotype correlation in WNT7A mutations and because it demonstrates that the G204S mutation may be associated with both AARRS and Fuhrmann phenotypes.     

Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition

N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.     

陕南早寒武世具口部的磷酸盐化Punctatus及其胚胎化石

报道陕西南部灯影组宽川铺段地层中发现的Punctatus锥体标本、保留精美软组织特征的口部标本和可能的胚胎标本。对Punctatus软组织及整体形态功能研究表明,Punctatus在分类上可能更接近于腔肠动物的水螅型,代表初具原始触手的腔肠动物早期演化类型。在上万枚与Punctatus共生的球状化石中,发现若干枚可能的原肠期胚胎及胚胎发育晚期标本,在此基础上提出PunctatusemeiensisHe,1980花冠状口部可能经历的胚胎发育序列。     

Structurally Distinct Ligands Rescue Biogenesis Defects of the KATP Channel Complex via a Converging Mechanism

Small molecules that correct protein misfolding and misprocessing defects offer a potential therapy for numerous human diseases. However, mechanisms underlying pharmacological correction of such defects, especially in heteromeric complexes with structurally diverse constituent proteins, are not well understood. Here we investigate how two chemically distinct compounds, glibenclamide and carbamazepine, correct biogenesis defects in ATP-sensitive potassium (K_ATP) channels composed of sulfonylurea receptor 1 (SUR1) and Kir6.2. We present evidence that despite structural differences, carbamazepine and glibenclamide compete for binding to K_ATP channels, and both drugs share a binding pocket in SUR1 to exert their effects. Moreover, both compounds engage Kir6.2, in particular the distal N terminus of Kir6.2, which is involved in normal channel biogenesis, for their chaperoning effects on SUR1 mutants. Conversely, both drugs can correct channel biogenesis defects caused by Kir6.2 mutations in a SUR1-dependent manner. Using an unnatural, photocross-linkable amino acid, azidophenylalanine, genetically encoded in Kir6.2, we demonstrate in living cells that both drugs promote interactions between the distal N terminus of Kir6.2 and SUR1. These findings reveal a converging pharmacological chaperoning mechanism wherein glibenclamide and carbamazepine stabilize the heteromeric subunit interface critical for channel biogenesis to overcome defective biogenesis caused by mutations in individual subunits.     

Yeast Translation Elongation Factor-1A Binds Vacuole-localized Rho1p to Facilitate Membrane Integrity through F-actin Remodeling

Rho GTPases are molecular switches that modulate a variety of cellular processes, most notably those involving actin dynamics. We have previously shown that yeast vacuolar membrane fusion requires re-organization of actin filaments mediated by two Rho GTPases, Rho1p and Cdc42p. Cdc42p initiates actin polymerization to facilitate membrane tethering; Rho1p has a role in the late stages of vacuolar fusion, but its mode of action is unknown. Here, we identified eEF1A as a vacuolar Rho1p-interacting protein. eEF1A (encoded by the TEF1 and TEF2 genes in yeast) is an aminoacyl-tRNA transferase needed during protein translation. eEF1A also has a second function that is independent of translation; it binds and organizes actin filaments into ordered cable structures. Here, we report that eEF1A interacts with Rho1p via a C-terminal subdomain. This interaction occurs predominantly when both proteins are in the GDP-bound state. Therefore, eEF1A is an atypical downstream effector of Rho1p. eEF1A does not promote vacuolar fusion; however, overexpression of the Rho1p-interacting subdomain affects vacuolar morphology. Vacuoles were destabilized and prone to leakage when treated with the eEF1A inhibitor narciclasine. We propose a model whereby eEF1A binds to Rho1p-GDP on the vacuolar membrane; it is released upon Rho1p activation and then bundles actin filaments to stabilize fused vacuoles. Therefore, the Rho1p-eEF1A complex acts to spatially localize a pool of eEF1A to vacuoles where it can readily organize F-actin.     

Phosphatized rare star-like mouth disc of Punctatus and its functional morphology from the earliest Cambrian of the South Shaanxi China

The Meishucun stage is the prelude in decipher-ing the Cambrian Explosion. In this prominent stage, rapid radioactive evolution and body-plan innovation have taken place and different associations of organism have been shaped. In this paper we report several 3D-preserved rare star-like fossils with finely preserved soft tissues which were recovered from the Kuanchuanpu Member of the Dengying Formation in South Shaanxi, China in 2003. By studying on functional morphology and analogy with mouthpart of Punctatus, there are evidences that this star-like organism approaches the coelenterates in systematic classification and the centre of star-like organism is its mouth. The appearance of coelenterates marks the real beginning of metazoan evolution. Therefore, it has the prominent position in the origin and evolutionary history of organisms. Perhaps the star-like organism represents the early types of coelenterate with original tentacles. These new materials provide new evidence for the origin, evolution and the functional evolution of the metazoan during the early stage of the Cambrian Explosion.     

Favositidae (Tabulata) from Emsian to Middle Devonian limestones of the Tamworth Group (N.S.W., Australia)

Several different species and species groups of the familiy Favositidae from the Emsian and Middle Devonian limestones of the Tamworth Group (N.S.W., Australia) are described. The Emsian Sulcor Limestone Member yieldedFavosites sp. aff.F. basalticus (Goldfuss, 1826),Favosites sp. aff.F. salebrosus Etheridge, 1899,Favosites stellaris Chernyshev, 1937,Squameofavosites nitidus (Chapman, 1914),Sq. bryani (Jones, 1937),Pachyfavosites rariporosus Dubatolov, 1963, andP. tumulosus Yanet, 1965. The Middle Devonian Moore Creek Limestone Member yieldedFavosites ex gr.goldfussi D’Orbigny, 1850, exclusively. In the Emsian limestones occur favositids in a wide array of different facies, with most being found in stratified biostromes and in bedded nodular limestones. In the Middle Devonian most favositids are found in nodular and lumpy limestones which occur at the base and at the top of some successions      

A NEW AZHDARCHOID PTEROSAUR FROM THE CRATO FORMATION (LOWER CRETACEOUS,APTIAN?) OF BRAZIL

Abstract: A partial pterosaur skull from the Nova Olinda Member of the Crato Formation (Lower Cretaceous, Aptian?) represents a new edentulous pterodactyloid, Lacusovagus magnificens gen. et sp. nov. The absence of teeth and a large nasoantorbital fenestra suggest assignment to Azhdarchoidea, and the combination of a particularly short, crestless and shallow rostrum and laterally flared jaw margins distinguish it from other azhdarchoid taxa. The position of the new form within Azhdarchoidea is problematic: Lacusovagus is distinguished from Tapejaridae in its straight, as opposed to ventrally displaced, jaw tip and absence of a premaxillary crest; from thalassodromids by the absence of a premaxillary crest; and from Azhdarchidae by the short length of the rostrum and shallow posterodorsal extension of the premaxilla. Lacusovagus shares a shallow, crestless rostrum and a slender posterodorsal premaxillary extension with Jiufotang Formation azhdarchoids such as Chaoyangopterus and Jidapterus. The position of these genera within Azhdarchoidea is controversial, but the suite of plesiomorphic and derived azhdarchoid characters in each suggests a placement between Tapejaridae and Neoazhdarchia. Further research is required, however, to determine the relationships of these genera both to each other and to other azhdarchoids. The new taxon elevates the faunal similarity found between the roughly contemporaneous Jiufotang and Crato formations and continues the pattern of Crato Formation azhdarchoids being much larger than those from the Jehol Group. It also has jaws at least 67 and 55 per cent longer, respectively, than those of the largest azhdarchoids and ornithocheirids from the Crato pterosaur assemblage, making Lacusovagus the largest pterosaur known from this unit.     

柴达木盆地冷湖地区中-晚始新世化石轮藻LAMPROTHAMNIUM GANCHAIGOUENSIS 组合带及其层序生物地层学意义

柴达木盆地冷湖构造的一些岩屑古生物分析发现,下干柴沟组上段存在一明显的化石轮藻Lamprothamnium ganchaigouensis组合带,而且这一组合带底界与下干柴沟组上段与下段的地质分界相当。在地震时间剖面上,通过井间追层及化石对比,发现这一化石组合带底界均与T4地震标准层相对应,形成了一个地震层序界面(等时界面)。因此,通过生物地层学与地震地层学的综合研究,可建立层序生物地层单元,具有层序生物地层学意义;地震与古生物资料的联合横向对比还可以帮助评估化石层位和标定地震标准层的相对位置,在生产实践中可节约成本,提高地层对比效率。