Analysis of conformational motions and related key residue interactions responsible for a specific function of proteins with elastic network model

Protein collective motions play a critical role in many biochemical processes. How to predict the functional motions and the related key residue interactions in proteins is important for our understanding in the mechanism of the biochemical processes. Normal mode analysis (NMA) of the elastic network model (ENM) is one of the effective approaches to investigate the structure-encoded motions in proteins. However, the motion modes revealed by the conventional NMA approach do not necessarily correspond to a specific function of protein. In the present work, a new analysis method was proposed to identify the motion modes responsible for a specific function of proteins and then predict the key residue interactions involved in the functional motions by using a perturbation approach. In our method, an internal coordinate that accounts for the specific function was introduced, and the Cartesian coordinate space was transformed into the internal/Cartesian space by using linear approximation, where the introduced internal coordinate serves as one of the axes of the coordinate space. NMA of ENM in this internal/Cartesian space was performed and the function-relevant motion modes were identified according to their contributions to the specific function of proteins. Then the key residue interactions important for the functional motions of the protein were predicted as the interactions whose perturbation largely influences the fluctuation along the internal coordinate. Using our proposed methods, the maltose transporter (MalFGK₂) from E. Coli was studied. The functional motions and the key residue interactions that are related to the channel-gating function of this protein were successfully identified.     

囊萼花属─—中国玄参科新记录属及—新种

报道了我国玄参科的一个新记录属──囊萼花属ＣｙｒｔａｎｄｒｏｍｏｅａＺｏｌｌ，该属为印度－马来西亚分布，它经过泰国北部，缅甸与我国发生连系，到达我国云南贡山、屏边、金平。全世界有１１—１２种，我国（云南）首次记录两种，其中一种为新种。     

气候变化下中国八种梧桐属树种潜在适生区模拟

中国梧桐属（Firmiana）在世界梧桐属中占比较大，且除梧桐外其余种均为中国特有且分布范围狭窄的植物种，灭绝风险大，研究气候变化对中国梧桐属树种的影响对于维护生物多样性具有重要的意义。结合多时期第六次国际气候耦合模式比较计划（CMIP6）气候变量数据和中国八种梧桐属树种的分布数据，基于R语言kuenm程序包优化的最大熵（Maxent）模型模拟分析中国八种梧桐属树种在多尺度下的潜在适生区，得出梧桐属最适宜的模拟尺度、潜在适生区的面积变化和迁移方向、梧桐属多样性保护关键区域及保护空缺。结果表明：（1）梧桐属最适宜的模拟尺度为亚洲；（2） Maxent模型的接收者操作特征曲线下面积（AUC）值均大于0.9，表明模型对梧桐属潜在适生区预测结果具有较高准确度；（3）气候变化影响下除云南梧桐（Firmiana major）外其它树种的潜在适生区都将在未来有所扩大；（4）中国八种梧桐属树种潜在适生区迁移方向主要为东西向，南北向大跨度迁移较少，纬度变化不大；（5）丹霞梧桐（Firmiana danxiaensis）的稳定潜在适生区最小；（6）中国梧桐属多样性保护关键区域主要分布于广西壮族自治区及云南、广东、海南等省区；（7）中国梧桐属多样性保护空缺区域主要分布于广西壮族自治区中部及海南省北部；（8）梧桐属多样性保护关键区域正在为人造地表所侵蚀。研究分析气候变化对中国八种梧桐属树种的影响及其潜在适生区变化、中国梧桐属多样性保护状态，可为中国梧桐属建立多样性保护廊道提供相关建议，为制定多样性保护规划及相应措施提供参考。     

Identifying a Kinase Network Regulating FGF14:Nav1.6 Complex Assembly Using Split-Luciferase Complementation

Kinases play fundamental roles in the brain. Through complex signaling pathways, kinases regulate the strength of protein:protein interactions (PPI) influencing cell cycle, signal transduction, and electrical activity of neurons. Changes induced by kinases on neuronal excitability, synaptic plasticity and brain connectivity are linked to complex brain disorders, but the molecular mechanisms underlying these cellular events remain for the most part elusive. To further our understanding of brain disease, new methods for rapidly surveying kinase pathways in the cellular context are needed. The bioluminescence-based luciferase complementation assay (LCA) is a powerful, versatile toolkit for the exploration of PPI. LCA relies on the complementation of two firefly luciferase protein fragments that are functionally reconstituted into the full luciferase enzyme by two interacting binding partners. Here, we applied LCA in live cells to assay 12 kinase pathways as regulators of the PPI complex formed by the voltage-gated sodium channel, Nav1.6, a transmembrane ion channel that elicits the action potential in neurons and mediates synaptic transmission, and its multivalent accessory protein, the fibroblast growth factor 14 (FGF14). Through extensive dose-dependent validations of structurally-diverse kinase inhibitors and hierarchical clustering, we identified the PI3K/Akt pathway, the cell-cycle regulator Wee1 kinase, and protein kinase C (PKC) as prospective regulatory nodes of neuronal excitability through modulation of the FGF14:Nav1.6 complex. Ingenuity Pathway Analysis shows convergence of these pathways on glycogen synthase kinase 3 (GSK3) and functional assays demonstrate that inhibition of GSK3 impairs excitability of hippocampal neurons. This combined approach provides a versatile toolkit for rapidly surveying PPI signaling, allowing the discovery of new modular pathways centered on GSK3 that might be the basis for functional alterations between the normal and diseased brain.     

Modelling Infectious Hematopoietic Necrosis Virus Dispersion from Marine Salmon Farms in the Discovery Islands,British Columbia,Canada

Finite volume ocean circulation and particle tracking models are used to simulate water-borne transmission of infectious hematopoietic necrosis virus (IHNV) among Atlantic salmon (Salmo salar) farms in the Discovery Islands region of British Columbia, Canada. Historical simulations for April and July 2010 are carried out to demonstrate the seasonal impact of river discharge, wind, ultra-violet (UV) radiation, and heat flux conditions on near-surface currents, viral dispersion and survival. Numerical particles released from infected farm fish in accordance with IHNV shedding rates estimated through laboratory experiments are dispersed by model oceanic flows. Viral particles are inactivated by ambient UV radiation levels and by the natural microbial community at rates derived through laboratory studies. Viral concentration maps showing temporal and spatial changes are produced and combined with lab-determined minimum infectious dosages to estimate the infective connectivity among farms. Results demonstrate that neighbouring naïve farms can become exposed to IHNV via water-borne transport from an IHNV diseased farm, with a higher risk in April than July, and that many events in the sequence of farm outbreaks in 2001-2002 are consistent with higher risks in our farm connectivity matrix. Applications to other diseases, transfers between farmed and wild fish, and the effect of vaccinations are also discussed.     

Survival rates of mutant genes under artificial selection using individual and family information

We have used diffusion and branching process methods to investigate fixation rates, probabilities of survival per generation, and times to fixation of mutant genes under different selection methods incorporating individual and family information. Diffusion approximations fit well to simulated results even for large selection coefficients. Methods that give much weight to family information, such as BLUP evaluation which is widely used in animal breeding, reduce fixation rates of mutant genes because of the reduced effective population sizes. In general, it is observed that even mutants with relatively small heterozygous effects (say 0.1 phenotypic standard deviation) are practically ‘safe’ (i.e. their probability of loss from one generation to the next is smaller than, say, 10%) after just a few generations, typically less than 10. For methods of selection with larger effective size, such as within-family selection, the mutant is ‘safe’ in the population somewhat earlier but eventual fixation takes a longer time. Finally we evaluate the amount by which the use of marker assisted selection reduces the fixation probability of newly arisen mutants.