P300 Interacted With N-Myc and Regulated Its Protein Stability via Altering Its Post-Translational Modifications in Neuroblastoma

MYCN amplification is an independent risk factor for poor prognosis in neuroblastoma (NB), but its protein product cannot be directly targeted because of protein structure. Thus, this study aimed to explore novel ways to indirectly target N-Myc by regulating its post-translational modifications (PTMs) and therefore protein stability. N-Myc coimmunoprecipitation combined with HPLC–MS/MS identified 16 PTM residues and 114 potential N-Myc-interacting proteins. Notably, both acetylation and ubiquitination were identified on lysine 199 of N-Myc. We then discovered that p300, which can interact with N-Myc, modulated the protein stability of N-Myc in MYCN-amplified NB cell lines and simultaneously regulated the acetylation level and ubiquitination level on lysine-199 of N-Myc protein in vitro. Furthermore, p300 correlated with poor prognosis in NB patients. Taken together, p300 can be considered as a potential therapeutic target to treat MYCN-amplified NB patients, and other identified PTMs and interacting proteins also provide potential targets for further study.     

基于MSPA-连接度-空间句法的生态保护空间及优先级识别——以苏锡常地区为例

随着城市化进程的加快,对生态保护空间(Ecological Protect Area,EPA)进行优先级识别已经成为保护生物多样性,缓解城市生态压力,提高土地利用效率的重要方法之一。以苏锡常地区为例,通过形态空间格局分析(Morphological Spatial Pattern Analysis,MSPA)确定EPA,进而采用景观连接度方法对其优先级进行识别,以优先级较高的林地和水域为"源地",构建EPA网络;同时由于景观连接度方法在识别优先级时,未能体现EPA对物种决策的非等权重影响,因此本研究引入空间句法进一步对EPA进行优先级识别。结果显示:1)苏锡常地区EPA中编号1、2的林地以及太湖的优先级最高,是区域网络的3个中心,需要优先保护;2)引入空间句法的优先级识别结果与基于景观连接度的优先级识别结果存在明显差异,后者优先级较高的8个EPA,在引入空间句法后优先级降低1—2个等级;后者优先级较低的4个EPA的优先级则上升了2个等级。同时也表明:基于连接度-空间句法的EPA优先级识别方法能够反映不同景观要素对物种决策行为的非等权重影响,强化了生态要素的空间配置的生态效应,为明确关键性生态空间,提供了有效的方法补充,对保护生物多样性和维系区域生态安全具有重要意义。     

Detecting early-warning signals for influenza A pandemic based on protein dynamical network biomarkers

The outbreak of influenza A comes from a relatively stable state is a critical phenomenon on epidemic. In this paper, influenza A varying from different states is studied in the method of dynamical network biomarkers (DNB). Through studying DNB of influenza A virus protein, we can detect the warning signals of outbreak for influenza A and obtain a composite index. The composite index varies along with the state of pandemic influenza, which gives a clue showing the turn point of outbreak. The low value (<1) steady state of the composite index means influenza A is normally in the relatively steady stage. Meanwhile, if the composite index of a certain year increases by more than 0.8 relative to the previous year and it is less than 1 and it increases sharply and reaches a peak being larger than 1 in next year, it means the year is normal in the critical state before outbreak and the next year is normally in the outbreak state. Therefore, we can predict the outbreak of influenza A and identify the critical state before influenza A outbreak or outbreak state by observing the variation of index value.     

基于多尺度协同的长沙市生态网络构建与层级优化

城市化背景下人类与自然环境的矛盾呈现出多尺度、层级化特征，而传统生态网络的构建方式较少考虑不同尺度下生态要素的关系，无法从区域落实到中心城区，难以形成系统性的解决方案。研究在综合梳理各尺度生态网络构建方法的基础上，以长沙市为例，基于形态学空间格局分析（Morphological Spatial Pattern Analysis，MSPA）、景观连通性原理和生态斑块重要性评价识别生态源地，并通过多层级生态阻力面的确定，综合运用最小费用路径（Least-cost path method，LCP）、电路理论、层级传导理论、尺度嵌套等方法对市域、都市区、中心城区的生态网络进行了协同构建和层级优化，最后基于不同尺度生态网络的特点应用并落实到多层级的国土空间规划体系中。研究结果表明：（1）长沙市域生态网络和都市区生态网络具有较好的层级嵌套特征；共识别两尺度生态叠合源地14个、生态叠合廊道15条，主要通过中心城区内的湘江、浏阳河和捞刀河部分河段与外围生态绿圈相衔接，形成"外环内楔"的空间格局。（2）确定市域重要廊道、市域潜在廊道、生态叠合廊道、都市区重要廊道、都市区潜在廊道的核心保护面积共501.14 km²，并提取位于生态廊道核心保护区范围内的生态夹点和生态障碍点，以进一步落实生态保护修复策略。（3）得到具有重要生态连通功能的中心城区生态绿道长度441.2 km，生态修复单元56个，并结合生态阻力值划分为5级进行针对性修复。（4）基于不同尺度生态网络的衔接、嵌套，最终构建"市域总体生态安全格局-都市区城市生态空间发展格局-以城市绿道为基础的中心城区生态修复单元"，并与不同层级的国土空间规划体系相对应。研究结果将为以大城市为中心的跨尺度生态系统修复和生态安全格局构建提供科学参考。     

小叶锦鸡儿灌丛化对典型草原群落结构与生态系统功能的影响

草原灌丛化是全球干旱半干旱地区面临的重要生态问题。灌丛化对草原生态系统结构与功能的影响较为复杂, 有待于在更广泛的区域开展研究。该研究在内蒙古锡林郭勒典型草原选择轻度、中度和重度灌丛化草地, 通过群落调查, 结合植物功能性状和土壤理化性质观测, 研究了小叶锦鸡儿(Caragana microphylla)灌丛化对草原群落结构(物种多样性、功能多样性和功能群组成)和生态系统功能(初级生产力、植被和土壤养分库)的影响。结果表明: 1)不同程度灌丛化草地的物种丰富度、功能性状多样性和群落加权性状平均值差异显著, 其中, 中度灌丛化草地的物种多样性和功能多样性较高, 表明一定程度的灌丛化有利于生物多样性维持。2)重度灌丛化草地的地上净初级生产力(ANPP)显著高于轻度和中度灌丛化草地, 其原因主要是随着灌丛化程度加剧, 群落内一/二年生草本植物显著增加, 而多年生禾草和多年生杂类草显著减少。三个灌丛化草地的植被叶片和土壤碳、氮库差异均不显著。3)灌丛化对草原生态系统功能包括ANPP、植被和土壤养分库均没有直接的影响, 而是通过影响功能群组成、土壤理化性质和功能多样性, 间接地影响生态系统功能; 灌丛化导致功能群发生替代和土壤旱碱化是最重要的生物和非生物因素。     

Switching between forest and trees: Opposite relationship of progesterone and testosterone to global–local processing

Sex differences in attentional selection of global and local components of stimuli have been hypothesized to underlie sex differences in cognitive strategy choice. A Navon figure paradigm was employed in 32 men, 41 naturally cycling women (22 follicular, 19 luteal) and 19 users of oral contraceptives (OCs) containing first to third generation progestins in their active pill phase. Participants were first asked to detect targets at any level (divided attention) and then at either the global or the local level only (focused attention). In the focused attention condition, luteal women showed reduced global advantage (i.e. faster responses to global vs. local targets) compared to men, follicular women and OC users. Accordingly, global advantage during the focused attention condition related significantly positively to testosterone levels and significantly negatively to progesterone, but not estradiol levels in a multiple regression model including all naturally cycling women and men. Interference (i.e. delayed rejection of stimuli displaying targets at the non-attended level) was significantly enhanced in OC users as compared to naturally cycling women and related positively to testosterone levels in all naturally cycling women and men. Remarkably, when analyzed separately for each group, the relationship of testosterone to global advantage and interference was reversed in women during their luteal phase as opposed to men and women during their follicular phase. As global processing is lateralized to the right and local processing to the left hemisphere, we speculate that these effects stem from a testosterone-mediated enhancement of right-hemisphere functioning as well as progesterone-mediated inter-hemispheric decoupling.     

The structure and function of phytochrome A: the roles of the entire molecule and of its various parts

Phytochrome A is readily cleavable by proteolytic agents to yield an amino-terminal fragment of 66 kilodalton (kDa), which consists of residues 1 to approximately 600, and a dimer of the carboxy-terminal 55-kDa fragment, from residue 600 or so to the carboxyl terminus. The former domain, carrying the tetrapyrrole chromophore, has been studied extensively because of its photoactivity, while less attention has been paid to the non-chromophoric portion until quite recently. However, the evidence gathered to date suggests that this domain is also of great improtance. We present here a review of the structure and the biochemical and physiological functions of the two domains, of parts of these domains, and of the cooperation between them.     

De novo inference of protein function from coarse‐grained dynamics

Inference of molecular function of proteins is the fundamental task in the quest for understanding cellular processes. The task is getting increasingly difficult with thousands of new proteins discovered each day. The difficulty arises primarily due to lack of high‐throughput experimental technique for assessing protein molecular function, a lacunae that computational approaches are trying hard to fill. The latter too faces a major bottleneck in absence of clear evidence based on evolutionary information. Here we propose a de novo approach to annotate protein molecular function through structural dynamics match for a pair of segments from two dissimilar proteins, which may share even <10% sequence identity. To screen these matches, corresponding 1 µs coarse‐grained (CG) molecular dynamics trajectories were used to compute normalized root‐mean‐square‐fluctuation graphs and select mobile segments, which were, thereafter, matched for all pairs using unweighted three‐dimensional autocorrelation vectors. Our in‐house custom‐built forcefield (FF), extensively validated against dynamics information obtained from experimental nuclear magnetic resonance data, was specifically used to generate the CG dynamics trajectories. The test for correspondence of dynamics‐signature of protein segments and function revealed 87% true positive rate and 93.5% true negative rate, on a dataset of 60 experimentally validated proteins, including moonlighting proteins and those with novel functional motifs. A random test against 315 unique fold/function proteins for a negative test gave >99% true recall. A blind prediction on a novel protein appears consistent with additional evidences retrieved therein. This is the first proof‐of‐principle of generalized use of structural dynamics for inferring protein molecular function leveraging our custom‐made CG FF, useful to all. Proteins 2014; 82:2443–2454. © 2014 Wiley Periodicals, Inc.     

Choice of Smoothing Parameters for Direct Kernels in Discrimination

Direct kernels, due to LAUDER (1983), as an alternative to the indirect kernel method in discriminant analysis are considered. It is shown that direct kernels may be based on any kernel function known in discrete density estimation. The choice of smoothing parameters is based on general loss functions and a family of loss functions which are specific for the discrimination problem is introduced. Examples with distance dependent and distance independent smoothing parameters are given to illustrate the applicability.