Pathological polyQ expansion does not alter the conformation of the Huntingtin-HAP40 complex

1. Download : Download high-res image (294KB)
2. Download : Download full-size image

     

我国三大城市群地区城市和农业用地地表热环境效应对比研究

以大中小城市协同发展为特征的城市群已成为我国城市化发展的主要形式，城市化和农业作为城市群地区最主要的土地利用活动，其气候效应是国际研究的热点。然而过去研究多关注大城市的热岛效应，对更为普遍的农业活动以及中小城市城市化的气候效应认识十分薄弱。基于MODIS地表温度数据，以自然林地为参照，提出了一种可逐像元估算土地利用地表热环境效应的新方法，进而对比分析了我国三大城市群地区（京津冀、长三角和珠三角）城市和农业用地地表热环境效应及其驱动因子差异。结果表明各城市群白天城市热岛效应明显，地级以上城市年平均热岛强度达3.2℃以上，但最强热岛均未发生在核心城市。夜晚热岛效应明显减弱，京津冀和长三角部分城市甚至出现冷岛效应。农业用地在白天亦表现出明显的增温效应，特别是在京津冀地区，而在夜晚除珠三角城市群外，降温效应明显，京津冀和长三角地区平均降温2.3℃和0.7℃。虽然城市用地平均增温强度大于农业用地，但农业用地因面积优势对区域温度变化起控制作用。白天城市和农业用地整体导致各城市群温度明显增加，京津冀增温最高（4.0℃），夜晚二者导致长三角和京津冀地区平均温度降低。研究还发现各城市群城市和农业用地地表热环境效应时空异质性极大，主要受植被、地表反照率、气候背景和人口密度控制。本文对制定缓解气候变化的土地利用策略具有重要的指导意义。     

Targeting of extracellular protein–protein interactions with macrocyclic peptides

Targeting of extracellular protein–protein interactions (PPI) is emerging as a major application for de novo discovered macrocyclic peptides. Modern discovery platforms can routinely identify macrocyclic peptide ligands capable of highly selective modulation of extracellular signaling pathways; amenability to chemical synthesis and natural modularity of peptides additionally provides an avenue for their further structural elaboration, while the challenge of cell internalization can be minimized. Here, we discuss the recent progress in targeting extracellular PPIs with macrocyclic peptides by focusing on a number of recent case studies. We analyze the scope and potential limitations of the discovery systems in identifying functional macrocyclic ligands. We also highlight the recent technical advancements allowing for a more streamlined discovery pipeline and our brief perspective in this field.     

Convenient and Efficient Syntheses of Oligodeoxyribonucleotides Containing O 6-(Carboxymethyl)Guanine and O 6-(4-Oxo-4-(3-Pyridyl)Butyl)Guanine

O ⁶-(carboxymethyl)guanine (O ⁶-CMG) and O ⁶-(4-oxo-4-(3-pyridyl)butyl)guanine (O ⁶-pobG) are toxic lesions formed in DNA following exposure to alkylating agents. O ⁶-CMG results from exposure to nitrosated glycine or nitrosated bile acid conjugates and may be associated with diets rich in red meat. O ⁶-pobG lesions are derived from alkylating agents found in tobacco smoke. Efficient syntheses of oligodeoxyribonucleotides (ODNs) containing O ⁶-CMG and O ⁶-pobG are described that involve nucleophilic displacement by the appropriate alcohol on a common synthetic ODN containing the reactive base 2-amino-6-methylsulfonylpurine. ODNs containing O ⁶-pobG and O ⁶-CMG were found to be good substrates for the S. pombe alkyltransferase-like protein Atl1.

[Supplemental materials are available for this article. Go to the publisher's online edition of Nucleosides, Nucleotides & Nucleic Acids to view the free supplemental file.]     

Alternative Splicing Products of the Gene for a Human Nuclear Actin-related Protein,hArpNβ/Baf53, that Encode a Protein Isoform,hArpNβS,in the Cytoplasm

A human nuclear actin-related protein, hArpNβ/Baf53, is a component of chromatin remodeling and histone acetyltransferase complexes. We identified two alternative splicing products of the gene for hArpNβ/Baf53. They encoded a protein isoform, hArpNβS; and its fusion product with green fluorescent protein was to be found in the cytoplasm, not the nucleus. The isoforms may contribute to functional regulation of these complexes.     

Rethinking protein aggregation and drug discovery in neurodegenerative diseases: Why we need to embrace complexity?

More than a century has passed since pathological protein aggregates were first identified in the brains of patients with neurodegenerative diseases (NDDs). Yet, we still do not have effective therapies to treat or slow the progression of these devastating diseases or diagnostics for early detection and monitoring disease progression. Herein, I reflect on recent findings that are challenging traditional views about the composition, ultrastructural properties, and diversity of protein pathologies in the brain, their mechanisms of formation and how we investigate and model pathological aggregation processes in the laboratory today. This article is an invitation to embrace the complexity of proteinopathies as an essential step to understanding the molecular mechanisms underpinning NDDs and to advance translational research and drug discovery in NDDs.     

Yes-associated protein is essential for proliferative vitreoretinopathy development via the epithelial-mesenchymal transition in retinal pigment epithelial fibrosis

This study was aim to investigate whether the progression of proliferative vitreoretinopathy (PVR) depended on the activation of Yes-associated protein (YAP) and the subsequent epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cell. The effect of YAP activation on retinal fibrosis in a PVR mouse model and in human ARPE-19 cells in vitro was studied. After treated with transforming growth factor-β2(TGF-β2), the expressions of fibrogenic molecules, YAP activation and the TGF-β2-Smad signalling pathway in ARPE-19 cells were detected by Western blot and immunocytochemical analyses. The effect of YAP on change in fibrosis and EMT was tested by knockdown experiment using verteporfin (YAP inhibitor). YAP was upregulated in the PVR mouse model and during TGF-β2–induced RPE cell EMT. In an in vivo study, verteporfin attenuated PVR progression in a mouse model. Additionally, YAP knockdown retained phenotype of RPE cells and ameliorated TGF-β2–induced migration, gel contraction and EMT in vitro. YAP knockdown inhibited the TGF-β2–induced upregulation of connective tissue growth factor (CTGF), smooth muscle actin (SMA-α) and fibronectin. YAP was essential for the TGF-β2–induced nuclear translocation and phosphorylation of Smad2/3. Our work provides direct evidence that YAP is an essential regulator of EMT and profibrotic responses in PVR and indicates that YAP inhibition could be a potential target in PVR therapeutic intervention.     

A current view on Tau protein phosphorylation in Alzheimer's disease

The functions of the neuronal microtubule-associated protein Tau in the central nervous system are regulated by manifold posttranslational modifications at more than 50 sites. Tau in healthy neurons carries multiple phosphate groups, mostly in its microtubule assembly domain. Elevated phosphorylation and aggregation of Tau are widely considered pathological hallmarks in Alzheimer’s disease (AD) and other tauopathies, triggering the quest for Tau posttranslational modifications in the disease context. However, the phosphorylation patterns of physiological and pathological Tau are surprisingly similar and heterogenous, making it difficult to identify specific modifications as therapeutic targets and biomarkers for AD. We present a concise summary of - and view on - important previous and recent advances in Tau phosphorylation analysis in the context of AD.