Cellular factors modulating the mechanism of tau protein aggregation

Pathological accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles, is a major hallmark of Alzheimer’s disease, the most prevalent neurodegenerative condition worldwide. In addition to Alzheimer’s disease, a number of neurodegenerative diseases, called tauopathies, are characterized by the accumulation of aggregated tau in a variety of brain regions. While tau normally plays an important role in stabilizing the microtubule network of the cytoskeleton, its dissociation from microtubules and eventual aggregation into pathological deposits is an area of intense focus for therapeutic development. Here we discuss the known cellular factors that affect tau aggregation, from post-translational modifications to molecular chaperones.     

Autoinhibition of TBCB regulates EB1-mediated microtubule dynamics

Tubulin cofactors (TBCs) participate in the folding, dimerization, and dissociation pathways of the tubulin dimer. Among them, TBCB and TBCE are two CAP-Gly domain-containing proteins that together efficiently interact with and dissociate the tubulin dimer. In the study reported here we showed that TBCB localizes at spindle and midzone microtubules during mitosis. Furthermore, the motif DEI/M-COO^? present in TBCB, which is similar to the EEY/F-COO^? element characteristic of EB proteins, CLIP-170, and α-tubulin, is required for TBCE–TBCB heterodimer formation and thus for tubulin dimer dissociation. This motif is responsible for TBCB autoinhibition, and our analysis suggests that TBCB is a monomer in solution. Mutants of TBCB lacking this motif are derepressed and induce microtubule depolymerization through an interaction with EB1 associated with microtubule tips. TBCB is also able to bind to the chaperonin complex CCT containing α-tubulin, suggesting that it could escort tubulin to facilitate its folding and dimerization, recycling or degradation.     

Inactivation of the p53 pathway in retinoblastoma

Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.     

Seismic Performance Assessment of High-rise Buildings Subjected to Near-Fault Ground Motion with Fling Effects

近断层地震地面运动区别于远场地震,具有滑冲效应特性和向前方向性效应特性.其中,具有单方向速度脉冲和阶跃式永久位移的滑冲效应对长周期结构影响较大.取1999年Turkey地震中台站SKR带有滑冲效应的近断层地震记录作为输入获得弹性和弹塑性反应谱,并详细分析具有不同大小线性特征周期的单自由度体系从线性发展到非线性的整个过程中滑冲效应的作用.以某典型的钢筋混凝土剪力墙高层建筑结构为例,具体研究近断层地震滑冲效应对结构抗震性能的影响.结果表明,近断层地震滑冲效应除了对较长周期的高层结构抗震性能具有不利影响之外,对可能产生较大非线性变形的短周期结构的影响同样不可忽视.     

The planetary increase of brightness during retrograde motion: An explanandum constructed ad explanantem

In Ancient Greek two models were proposed for explaining the planetary motion: the homocentric spheres of Eudoxus and the Epicycle and Deferent System. At least in a qualitative way, both models could explain the retrograde motion, the most challenging phenomenon to be explained using circular motions. Nevertheless, there is another explanandum: during retrograde motion the planets increase their brightness. It is natural to interpret a change of brightness, i.e., of apparent size, as a change in distance. Now, while according to the Eudoxian model the planet is always equidistant from the earth, according to the epicycle and deferent system, the planet changes its distance from the earth, approaching to it during retrograde motion, just as observed. So, it is usually affirmed that the main reason for the rejection of Eudoxus' homocentric spheres in favor of the epicycle and deferent system was that the first cannot explain the manifest planetary increase of brightness during retrograde motion, while the second can. In this paper I will show that this historical hypothesis is not as firmly founded as it is usually believed to be.     

Images of single-stranded nucleic acids by scanning tunnelling microscopy

The scanning tunnelling microscope has the potential to resolve the structure of biological molecules with atomic detail. Progress has been made in the imaging of dried, unshadowed double helices of DNA4-7 and in recording images of DNA under water. Also, images of unshadowed complexes of DNA with the RecA protein from Escherichia coli indicate that this technique may not be restricted to thin biological samples. Here we present images of polydeoxyadenylate molecules aligned in parallel, with their bases lying flat on a surface of highly oriented pyrolytic graphite and with their charged phosphodiester backbones protruding upwards. Based on these images, a molecular model has been built which suggests the presence of a hydrogen bond that could stabilize the parallel alignment. Our micrographs demonstrate the potential application of scanning tunnelling microscopy in structural studies of nucleic acids and provide evidence that it could be used to sequence DNA.