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.     

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      

Lipid droplet proteins and metabolic diseases

Lipid droplets (LDs) are ubiquitous cellular organelles for lipid storage which are composed of a neutral lipid core bounded by a protein decorated phospholipid monolayer. Although lipid storage is their most obvious function, LDs are far from inert as they participate in maintaining lipid homeostasis through lipid synthesis, metabolism, and transportation. Furthermore, they are involved in cell signaling and other molecular events closely associated with human disease such as dyslipidemia, obesity, lipodystrophy, diabetes, fatty liver, atherosclerosis, and others. The last decade has seen a great increase in the attention paid to LD biology. Regardless, many fundamental features of LD biology remain obscure. In this review, we will discuss key aspects of LD biology including their biogenesis, growth and regression. We will also summarize the current knowledge about the role LDs play in human disease, especially from the perspective of the dynamics of the associated proteins. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.     

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。     

陕南早寒武世早期Quadrapyrgites再研究

处于"寒武纪生命大爆发"序幕阶段的梅树村期,生物类群大规模辐射,身体构型快速革新,与前寒武纪生物群面貌明显不同.最近在陕南宁强宽川铺地区梅树村期地层中发现了大量五辐射Punctatus及部分四辐射四方塔形壳属Quadrapyrgites,其中包括1个新种Quadrnpyrgites undulatuscostalis sp.nov..在此基础上对Quadrapyrgites进行了属征补充.双胚层腔肠动物的出现标志着地球生命史的真后生动物演化开端,在生物起源演化历程上占据着关键的位置.本文为研究真后生动物起源演化、生物辐射、体型构建提供了重要实证.