Structural determinants specific for retromer protein sorting nexin 5 in regulating subcellular retrograde membrane trafficking

The endosomal trafficking of signaling membrane proteins, such as receptors, transporters and channels, is mediated by the retromer-mediated sorting machinery, composed of a cargo-selective vacuolar protein sorting trimer and a membrane-deforming subunit of sorting nexin proteins. Recent studies have shown that the isoforms, sorting nexin 5 (SNX5) and SNX6, have played distinctive regulatory roles in retrograde membrane trafficking. However, the molecular insight determined functional differences within the proteins remains unclear. We reported that SNX5 and SNX6 had distinct binding affinity to the cargo protein vesicular monoamine transporter 2 (VMAT2). SNX5, but not SNX6, specifically interacted with VMAT2 through the Phox domain, which contains an alpha-helix binding motif. Using chimeric mutagenesis, we identified that several key residues within this domain were unique in SNX5, but not SNX6, and played an auxiliary role in its binding to VMAT2. Importantly, we generated a set of mutant SNX6, in which the corresponding key residues were mutated to those in SNX5. In addition to the gain in binding affinity to VMAT2, their overexpression functionally rescued the altered retrograde trafficking of VMAT2 induced by siRNA-mediated depletion of SNX5. These data strongly suggest that SNX5 and SNX6 have different functions in retrograde membrane trafficking, which is determined by the different structural elements within the Phox domain of two proteins. Our work provides a new information on the role of SNX5 and SNX6 in the molecular regulation of retrograde membrane trafficking and vesicular membrane targeting in monoamine neurotransmission and neurological diseases.

Percutaneous endoscopic gastrostomy—Too often?Too late?Who are the right patients for gastrostomy?

Percutaneous endoscopic gastrostomy is an established method to provide nutrition to patients with restricted oral uptake of fluids and calories.Here,we review the methods,indications and complications of this procedure.While gastrostomy can be safely and easily performed during gastroscopy,the right patients and timing for this intervention are not always chosen.Especially in patients with dementia,the indication for and timing of gastrostomies are often improper.In this patient group,clear data for enteral nutrition are lacking;however,some evidence suggests that patients with advanced dementia do not benefit,whereas patients with mild to moderate dementia might benefit from early enteral nutrition.Additionally,other patient groups with temporary or permanent restriction of oral uptake might be a useful target population for early enteral nutrition to maintain mobilization and muscle strength.We plead for a coordinated study program for these patient groups to identify suitable patients and the best timing for tube implantation.

让粉质物料的装卸更加安全——高效活性药物成分在防爆炸容器中的装与卸，彻底解决了安全问题

新研发的，模块式粉质原材料真空和压力运输系统是一种移动式的原料桶清空系统，这是专门为高效活性药物成分的装卸而研发设计的解决方案。本文介绍了这一新的系统与传统的隔离室、密封隔离对接系统等拆卸方法的不同之处。

多恩比恩公共图书馆

多恩比恩公共图书馆是一个包含代际共享、会议和学习空间的建筑。致力于宣传阅读、语言实践、计算机化研究方法的探索以及全新的交流方式。多恩比恩市长Andrea Kaufmann高兴地表示:“新图书馆是多恩比恩文化和教育领域的一个里程碑。”城市背景建筑卵圆形的形态仿佛自然生成,在一众矩形建筑中脱颖而出。小径穿过建筑延伸至室外,成为公共活动空间。

Genomic,transcriptomic,and epigenomic analysis of a medicinal snake,Bungarus multicinctus,to provides insights into the origin of Elapidae neurotoxins

The many-banded krait,Bungarus multicinctus,has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia.Characterization of its venoms classified chief phyla of modern animal neurotoxins.However,the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome.Here,we present the 1.58 Gbp genome of B.multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp.Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications.The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins(3FTxs)from membrane tethering before the Colubroidea divergence.Subsequent expansion and mutations diversified and recruited these 3FTxs.After the cobra/krait divergence,the modern unit-B ofβ-bungarotoxin emerged with an extra cysteine residue.A subsequent point substitution in unit-A enabled theβ-bungarotoxin covalent linkage.The B.multicinctus gene expression,chromatin topological organization,and histone modification characteristics were featured by transcriptome,proteome,chromatin conformation capture sequencing,and ChIP-seq.The results highlighted that venom production was under a sophisticated regulation.Our findings provide new insights into snake neurotoxin research,meanwhile will facilitate antivenom development,toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.

Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.

Critical Behaviour of the Ising S=1/2 and S=1 Model on(3,4,6,4)and(3,3,3,3,6)Archimedean Lattices

We investigate the critical properties of the Ising S=1/2 and S=1 model on(3,4,6,4)and(34,6)Archimedean lattices.The system is studied through the extensive Monte Carlo simulations.We calculate the critical temperature as well as the critical point exponentsγ/ν,β/ν,andνbasing on finite size scaling analysis.The calculated values of the critical temperature for S=1 are kBTC/J=1.590(3),and kBTC/J=2.100(4)for(3,4,6,4)and(34,6)Archimedean lattices,respectively.The critical exponentsβ/ν,γ/ν,and 1/ν,for S=1 areβ/ν=0.180(20),γ/ν=1.46(8),and 1/ν=0.83(5),for(3,4,6,4)and 0.103(8),1.44(8),and 0.94(5),for(34,6)Archimedean lattices.Obtained results differ from the Ising S=1/2 model on(3,4,6,4),(34,6)and square lattice.The evaluated effective dimensionality of the system for S=1 are Deff=1.82(4),for(3,4,6,4),and Deff=1.64(5)for(34,6).

The ＂Loss＂ of Purity： Changes and Persistence in the Cultural Memory of the Cold Spring Pavilion

Ever since the Cold Spring Pavilion （Lengquan ting 冷泉亭） was built, it has been extolled by scholar-literati as a place of purity, where the dust of the mundane world could be cleansed by the cold spring water flowing beside it. For centuries, people tried to reinforce the image of the pavilion as an innocent haven through writing poems, stories, and essays about their visits there. But they were unaware, or refused to admit, that their admiration of the place also possessed the power to destroy whatever sacredness and serenity it stood for. This paper examines representations of the Cold Spring Pavilion in Chinese literature through the lens of a paradox that has haunted the pavilion since it was first built. The paper argues that, ever since the pavilion was built, it has, through its literary-historical representation, been slowly but inevitably absorbed or assimilated into what it had originally been built to fend off. Like the Cold Spring, which flowed into West Lake, the Cold Spring Pavilion, which was created to help people resist the temptations of city life, was inevitably absorbed into the very fabric of the city.