Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data

The ErbB signaling pathways, which regulate diverse physiological responses such as cell survival, proliferation and motility, have been subjected to extensive molecular analysis. Nonetheless, it remains poorly understood how different ligands induce different responses and how this is affected by oncogenic mutations. To quantify signal flow through ErbB‐activated pathways we have constructed, trained and analyzed a mass action model of immediate‐early signaling involving ErbB1–4 receptors (EGFR, HER2/Neu2, ErbB3 and ErbB4), and the MAPK and PI3K/Akt cascades. We find that parameter sensitivity is strongly dependent on the feature (e.g. ERK or Akt activation) or condition (e.g. EGF or heregulin stimulation) under examination and that this context dependence is informative with respect to mechanisms of signal propagation. Modeling predicts log‐linear amplification so that significant ERK and Akt activation is observed at ligand concentrations far below the K_d for receptor binding. However, MAPK and Akt modules isolated from the ErbB model continue to exhibit switch‐like responses. Thus, key system‐wide features of ErbB signaling arise from nonlinear interaction among signaling elements, the properties of which appear quite different in context and in isolation.     

MODELS OF CHARACTER DISPLACEMENT AND THE THEORETICAL ROBUSTNESS OF TAXON CYCLES

The appropriateness of the techniques used in modeling character displacement has been the focus of vigorous debate. In this paper, the three competing methods (the coevolutionarily stable community (CSC), the evolutionarily stable strategy (ESS), and quantitative genetic recursion (QGR)) are compared in models using a common ecological setting. Specific predictions of the CSC model have been used to understand features of character displacement among Cnemidophorous lizards on islands off Mexico, Anolis lizards in the Lesser Antilles and Galápagos finches. Nonetheless, the validity of the approach has been repeatedly questioned. Conceptually the three formalisms vary in the degree to which within species variability is allowed in the models. The predictions of the CSC are found not to be robust to even small violation of its fundamental assumption of absolute species monomorphy. We show by simulation and analytical observations that the CSC is not valid under frequency dependent selection, and that the ESS is the limiting case of QGR as intraspecific phenotypic variation goes to zero. Thus the ESS and the QGR models agree closely when the between-phenotype component (BPC) of the niche width is small. However, as the BPC increases, quantitative discrepancies between ESS and QGR predictions increase, although model behavior remains qualitatively similar. A fourth approach, termed “Quantitative Genetic Optimization” (QGO) analysis, is suggested, combining advantages of both the ESS and QGR. Although all approaches support the possibility of taxon cycles, the cycle patterns predicted are qualitatively different and strongly model dependent.     

基于山地-绿洲-荒漠系统的生态系统服务正负价值测算——以新疆玛纳斯河流域为例

基于不同生态单元分析生态系统服务正负价值有助于全面客观地了解生态系统服务的异质性。选择典型山地-绿洲-荒漠系统(Mountain-Oasis-Desert System,MODS)下的玛纳斯河流域作为研究区,以1990年、1995年、2000年、2005年、2010年及2015年Landsat系列遥感影像为数据源,采用修正后的生态系统服务价值系数对不同生态单元下的生态系统服务正负价值进行估算。结果表明:(1)1990—2015年玛纳斯河流域土地利用/覆被变化较为显著,耕地、水域及建设用地面积呈现增加趋势,林地、草地及未利用地面积呈减少趋势,其中耕地和未利用地面积变化最为剧烈,建设用地增幅最大,林地减幅最大。(2)研究时段内,研究区正向价值远高于负向价值,且净价值小幅度增加。正向价值在经历"增加-减少-减少-增加-增加"的变化过程后呈现增加趋势,并呈现山地区绿洲区荒漠区的特征;各负向价值均表现为不同程度的增大趋势,其中温室气体排放、化肥流失及水资源消耗是流域内最为突出的负向生态系统服务,三者价值之和占比在不同时间段上均达90%以上;净价值由研究初期的8947.89×10~6元增加至末期的10409.99×10~6元,年均增加0.65%。(3)人均生态系统服务净价值呈现下降趋势,流域环境压力增大。     

碳中和视角下基于主体功能区分类约束的国土空间分区优化模拟——以福建省为例

在推进新时代生态文明建设、确保区域社会经济绿色发展并如期实现碳达峰碳中和目标的发展导向下，基于主体功能区分类约束开展以低碳发展为牵引的多情景国土空间优化模拟研究具有重要意义。以国家生态文明试验区福建省为研究区，设定自然发展和低碳发展两种不同情景，针对不同类别主体功能区，设置差异化的碳排放量、经济效益和生态效益约束目标，在对用地需求进行预测的基础上，基于PLUS模型开展多情景下的国土空间分区优化模拟。结果表明：1）从用地规模和数量结构来看，低碳发展情景下的功能区用地结构更加符合低碳经济发展的要求，该情景在减缓碳源地增加速度的同时，能够降低碳汇地的减少速度，在保障区域经济发展用地需求的同时减少碳排放并降低生态环境影响；2）从用地布局来看，虽然不同情景下的用地结构存在一定差异，但从空间分布特征来看，各地类的变化规律基本与历史趋势基本相同，其中碳源地主要分布在临近海岸线处海拔较低、地势平缓易开发的一侧，碳汇地主要集中在内陆区域海拔相对较高且地况较复杂的区域；3）从三类典型区域空间演变模式来看，农业生产区和生态保护区的变化较小，城镇建设区变化较为明显，城镇建设区和农业生产区主要功能用地分布较为集中且聚合度较高，生态保护区主要功能用地较为分散且一般呈破碎状。在不同发展情景下，国土空间格局中的碳源地不断扩张、碳汇地空间逐步受到挤压，应进一步发掘存量用地的潜力，推动土地资源的高效利用。     

Predicting the onset of filamentous bulking in biological wastewater treatment systems by exploiting image analysis information

The performance of the activated sludge process is limited by the ability of the sedimentation tank (1) to separate the activated sludge from the treated effluent and (2) to concentrate it. Apart from bad operating strategies or poorly designed clarifiers, settling failures can mainly be attributed to filamentous bulking. Image analysis is a promising technique that can be used for early detection of filamentous bulking. The aim of this paper is therefore twofold. Foremost, correlations are sought between image analysis information (i.e., the total filament length per image, the mean form factor, the mean equivalent floc diameter, the mean floc roundness and the mean floc reduced radius of gyration) and classical measurements (i.e., the Sludge Volume Index (SVI)). Secondly, this information is both explored and exploited in order to identify dynamic ARX and state space-type models. Their performance is compared based on two criteria.     

Molecular and physiological evidence suggests the existence of a system II-like pathway of ethylene production in non-climacteric<Emphasis Type="Italic"> Citrus</Emphasis> fruit

Mature citrus fruits, which are classified as non-climacteric, evolve very low amounts of ethylene during ripening but respond to exogenous ethylene by ripening-related pigment changes and accelerated respiration. In the present study we show that young citrus fruitlets attached to the tree produce high levels of ethylene, which decrease dramatically towards maturation. Upon harvest, fruitlets exhibited a climacteric-like rise in ethylene production, preceded by induction of the genes for 1-aminocyclopropane-1-carboxylate (ACC) synthase 1 (CsACS1), ACC oxidase 1 (CsACO1) and the ethylene receptor CsERS1. This induction was advanced and augmented by exogenous ethylene or propylene, indicating an autocatalytic system II-like ethylene biosynthesis. In mature, detached fruit, very low rates of ethylene production were associated with constitutive expression of the ACC synthase 2 (CsACS2) and ethylene receptor CsETR1 genes (system I). CsACS1 gene expression was undetectable at this stage, even following ethylene or propylene treatment, and CsERS1 gene expression remained constant, indicating that no autocatalytic response had occurred. The transition from system II-like behavior of young fruitlets to system I behavior appears to be under developmental control.Abbreviations ACC 1-Aminocyclopropane-1-carboxylate - CsACS1, CsACS2 ACC synthase - CsACO1 ACC oxidase - CsERS1, CsETR1 Ethylene receptors - DAFB Days after full bloom - 1-MCP 1-Methylcyclopropene     

Dynamic optimization of host defense, immune memory, and post-infection pathogen levels in mammals

When attacked by pathogens, higher vertebrates produce specific immune cells that fight against them. We here studied the host's optimal schedule of specific immune cell production. The damage caused by the pathogen increases with the pathogen amount in the host integrated over time. On the other hand, there is also a cost incurred by the production of specific immune cells, not only in terms of the energy needed to produce and maintain the cells, but also with respect to damages sustained by the host's body as a result of immune activity. The optimal strategy of the host is the one that minimizes the total cost, defined as a weighted sum of the damage caused by pathogens and the costs caused by the specific immune cells. The problem is solved by using Pontryagin's maximum principle and dynamic programming. The optimal defense schedule is typically as follows: In the initial phase after infection, immune cells are produced at the fastest possible rate. The amount of pathogen increases temporarily but is eventually suppressed. When the pathogen amount is suppressed to a sufficiently low level, the immune cell number decreases and converges to a low steady level, which is maintained by alternately switching between fastest production and no production. We examine the effect of time delay required to have fully active immune cells by comparing cases with different number of rate limiting steps before producing immune cells. We examine the effect of the duration of time (time delay) required before full-scale production of active immune cells by comparing cases with different numbers of rate-limiting steps before immune-cell production. We also discuss the role of immune memory based on the results of the optimal immune reaction.     

Estimating optimal profiles of genetic alterations using constraint-based models

Metabolic engineering involves application of recombinant DNA methods to manipulate metabolic networks to improve cellular properties. It is critical that the genetic alterations be performed in an optimal manner to maximize profit. In addition to the product yield, productivity consideration is also critical, especially for the production of bulk chemicals such as 1,3-propanediol. In this work, we demonstrate that it is suboptimal from the standpoint of productivity to induce genetic alteration at the start of the production process. A bi-level optimization scheme is formulated to determine the optimal temporal flux profile for the manipulated reaction. In the first case study, an optimal flux in the reaction catalyzed by glycerol kinase is determined to maximize the glycerol production at the end of a 6-h batch cultivation of Escherichia coli under aerobic conditions. The final glycerol concentration is 30% higher for the optimal flux profile compared with having an active flux during the entire batch. The effect of the mass transfer coefficient on the optimal profile and the glycerol concentration is also determined. In the second case study, the anaerobic batch fermentation of the ldh(-) strain of Escherichia coli is considered. The optimal flux in the acetate pathway is determined to maximize the final ethanol concentration. The optimal flux results in higher ethanol concentration (11.92 mmol L(-1)) compared to strains with no acetate flux (8.36 mmol L(-1)) and fully active acetate flux (6.22 mmol L(-1)). We also examine the effects of growth inhibition due to high ethanol concentrations and variations in final batch time on ethanol production.     

A cardiovascular-respiratory control system model including state delay with application to congestive heart failure in humans

This paper considers a model of the human cardiovascular-respiratory control system with one and two transport delays in the state equations describing the respiratory system. The effectiveness of the control of the ventilation rate is influenced by such transport delays because blood gases must be transported a physical distance from the lungs to the sensory sites where these gases are measured. The short term cardiovascular control system does not involve such transport delays although delays do arise in other contexts such as the baroreflex loop (see [46]) for example. This baroreflex delay is not considered here. The interaction between heart rate, blood pressure, cardiac output, and blood vessel resistance is quite complex and given the limited knowledge available of this interaction, we will model the cardiovascular control mechanism via an optimal control derived from control theory. This control will be stabilizing and is a reasonable approach based on mathematical considerations as well as being further motivated by the observation that many physiologists cite optimization as a potential influence in the evolution of biological systems (see, e.g., Kenner [29] or Swan [62]). In this paper we adapt a model, previously considered (Timischl [63] and Timischl et al. [64]), to include the effects of one and two transport delays. We will first implement an optimal control for the combined cardiovascular-respiratory model with one state space delay. We will then consider the effects of a second delay in the state space by modeling the respiratory control via an empirical formula with delay while the the complex relationships in the cardiovascular control will still be modeled by optimal control. This second transport delay associated with the sensory system of the respiratory control plays an important role in respiratory stability. As an application of this model we will consider congestive heart failure where this transport delay is larger than normal and the transition from the quiet awake state to stage 4 (NREM) sleep. The model can be used to study the interaction between cardiovascular and respiratory function in various situations as well as to consider the influence of optimal function in physiological control system performance.Supported by FWF (Austria) under grant F310 as a subproject of the Special Research Center F003 Optimization and ControlMathematics Subject Classification (2000): 92C30, 49J15     

Construction and maintenance of the optimal photosynthetic systems of the leaf, herbaceous plant and tree: an eco-developmental treatise

BACKGROUND AND AIMS: The paper by Monsi and Saeki in 1953 (Japanese Journal of Botany 14: 22-52) was pioneering not only in mathematical modelling of canopy photosynthesis but also in eco-developmental studies of seasonal changes in leaf canopies. SCOPE: Construction and maintenance mechanisms of efficient photosynthetic systems at three different scaling levels--single leaves, herbaceous plants and trees--are reviewed mainly based on the nitrogen optimization theory. First, the nitrogen optimization theory with respect to the canopy and the single leaf is briefly introduced. Secondly, significance of leaf thickness in CO2 diffusion in the leaf and in leaf photosynthesis is discussed. Thirdly, mechanisms of adjustment of photosynthetic properties of the leaf within the herbaceous plant individual throughout its life are discussed. In particular, roles of sugar sensing, redox control and of cytokinin are highlighted. Finally, the development of a tree is considered. CONCLUSIONS: Various mechanisms contribute to construction and maintenance of efficient photosynthetic systems. Molecular backgrounds of these ecologically important mechanisms should be clarified. The construction mechanisms of the tree cannot be explained solely by the nitrogen optimization theory. It is proposed that the pipe model theory in its differential form could be a potential tool in future studies in this research area.