New paradigm in protein function prediction for large scale omics analysis

Biological interpretation of large scale omics data, such as protein-protein interaction data and microarray gene expression data, requires that the function of many genes in a data set is annotated or predicted. Here the predicted function for a gene does not necessarily have to be a detailed biochemical function; a broad class of function, or low-resolution function, may be sufficient to understand why a set of genes shows the observed expression pattern or interaction pattern. In this Highlight, we focus on two recent approaches for function prediction which aim to provide large coverage in function prediction, namely omics data driven approaches and a thorough data mining approach on homology search results.     

稻纵卷叶螟卷叶有虫率与化蛹率关系的研究

探索利用稻纵卷叶螟 Cnaphalocrocis medinalis（Guenée）卷叶有虫率估测化蛹率的方法和途径。本文基于稻纵卷叶螟化蛹进度的田间调查数据,用化蛹率（y）和卷叶有虫率（x）分别拟合直线函数、一元二次函数、一元三次函数、对数函数、指数函数和幂函数6种不同模型。结果表明,以一元三次函数方法估计精度最高,误差最小,应用效果最好,并根据最优数学模型建立化蛹率（y）与卷叶有虫率（x）的关系速查表。生产中可以应用拟合的 最优数学模型对田间稻纵卷叶螟化蛹进度进行监测。     

Stability and the evolvability of function in a model protein

Functional proteins must fold with some minimal stability to a structure that can perform a biochemical task. Here we use a simple model to investigate the relationship between the stability requirement and the capacity of a protein to evolve the function of binding to a ligand. Although our model contains no built-in tradeoff between stability and function, proteins evolved function more efficiently when the stability requirement was relaxed. Proteins with both high stability and high function evolved more efficiently when the stability requirement was gradually increased than when there was constant selection for high stability. These results show that in our model, the evolution of function is enhanced by allowing proteins to explore sequences corresponding to marginally stable structures, and that it is easier to improve stability while maintaining high function than to improve function while maintaining high stability. Our model also demonstrates that even in the absence of a fundamental biophysical tradeoff between stability and function, the speed with which function can evolve is limited by the stability requirement imposed on the protein.     

A continued role for signaling functions in the early evolution of feathers

Persons and Currie (2015) argued against either flight, thermoregulation, or signaling as a functional benefit driving the earliest evolution of feathers; rather, they favored simple feathers having an initial tactile sensory function, which changed to a thermoregulatory function as density increased. Here, we explore the relative merits of early simple feathers that may have originated as tactile sensors progressing instead toward a signaling, rather than (or in addition to) a thermoregulatory function. We suggest that signaling could act in concert with a sensory function more naturally than could thermoregulation. As such, the dismissal of a possible signaling function and the presumption that an initial sensory function led directly to a thermoregulatory function (implicit in the title “bristles before down”) are premature.     

京津冀地区县域耕地景观多功能性评价

随着城镇化发展和农业产业化升级,耕地景观功能由单一的生产功能向经济功能、生态功能、文化功能拓展,耕地景观多功能性成为新的学术热点。已有研究往往侧重于探讨耕地功能的多指数耦合,缺乏耕地景观多重功能空间定量化与相互关联的分析。以京津冀地区为研究区,对耕地景观的粮食供给功能、生境维持功能、景观连通功能、土壤保持功能、景观美学功能和人口承载功能六项功能及其冷热点聚集区分别空间定量化,评价县域尺度耕地景观多功能性,并识别耕地景观多种功能的空间关联。研究结果表明,京津冀中部平原地区粮食供给功能显著,南部平原地区景观连通功能突出,燕山与太行山山脉土壤保持功能、维持生境功能最高,山前平原地带人口承载功能相对重要。2010年京津冀地区耕地景观功能总体呈现南高北低的分布格局,但功能高低值分布规律差异明显,各功能全部处于高值或低值的样本极少;耕地景观不同功能间的权衡与协同关系数量相当,景观连通功能与粮食供给功能呈现明显协同关系,而与土壤保持功能呈现较强权衡关联。     

Local function conservation in sequence and structure space

We assess the variability of protein function in protein sequence and structure space. Various regions in this space exhibit considerable difference in the local conservation of molecular function. We analyze and capture local function conservation by means of logistic curves. Based on this analysis, we propose a method for predicting molecular function of a query protein with known structure but unknown function. The prediction method is rigorously assessed and compared with a previously published function predictor. Furthermore, we apply the method to 500 functionally unannotated PDB structures and discuss selected examples. The proposed approach provides a simple yet consistent statistical model for the complex relations between protein sequence, structure, and function. The GOdot method is available online (http://godot.bioinf.mpi-inf.mpg.de).     

A novel empirical free energy function that explains and predicts protein-protein binding affinities

A free energy function can be defined as a mathematical expression that relates macroscopic free energy changes to microscopic or molecular properties. Free energy functions can be used to explain and predict the affinity of a ligand for a protein and to score and discriminate between native and non-native binding modes. However, there is a natural tension between developing a function fast enough to solve the scoring problem but rigorous enough to explain and predict binding affinities. Here, we present a novel, physics-based free energy function that is computationally inexpensive, yet explanatory and predictive. The function results from a derivation that assumes the cost of polar desolvation can be ignored and that includes a unique and implicit treatment of interfacial water-bridged interactions. The function was parameterized on an internally consistent, high quality training set giving R2=0.97 and Q2=0.91. We used the function to blindly and successfully predict binding affinities for a diverse test set of 31 wild-type protein-protein and protein-peptide complexes (R2=0.79, rmsd=1.2 kcal mol(-1)). The function performed very well in direct comparison with a recently described knowledge-based potential and the function appears to be transferable. Our results indicate that our function is well suited for solving a wide range of protein/peptide design and discovery problems.     

A new fitness function and its application on a five locus model

Summary A new fitness function is proposed. It is a balance function which results from a combination of a turnover function defining the expression of favourable genetic factors and a cost function describing the costs of metabolism. A favourable genetic factor is defined as the heterozygote state at a locus. Five loci with two alleles each are considered. In computer simulations various kinds of this function are investigated. Their influence on the genetic composition of a population in equilibrium, the number and types of equilibria and the mean fitness are reported. Free recombination and tight linkage are considered.     

AMP-activated protein kinase (AMPK) regulates autophagy,inflammation and immunity and contributes to osteoclast differentiation and functionabs

Osteoclasts are multinucleated giant cells, responsible for bone resorption. Osteoclast differentiation and function requires a series of cytokines to remove the old bone, which coordinates with the induction of bone remodelling by osteoblast-mediated bone formation. Studies have demonstrated that AMP-activated protein kinase (AMPK) play a negative regulatory role in osteoclast differentiation and function. Research involving AMPK, a nutrient and energy sensor, has primarily focused on osteoclast differentiation and function; thus, its role in autophagy, inflammation and immunity remains poorly understood. Autophagy is a conservative homoeostatic mechanism of eukaryotic cells, and response to osteoclast differentiation and function; however, how it interacts with inflammation remains unclear. Additionally, based on the regulatory function of different AMPK subunits for osteoclast differentiation and function, its activation is regulated by upstream factors to perform bone metabolism. This review summarises the critical role of AMPK-mediated autophagy, inflammation and immunity by upstream and downstream signalling during receptor activator of nuclear factor kappa-B ligand-induced osteoclast differentiation and function. This pathway may provide therapeutic targets for bone-related diseases, as well as function as a biomarker for bone homoeostasis.     

2000-2020年京津冀地区国土空间多功能权衡强度时空演变及影响机制

厘清国土空间多功能相互关系及影响因素,对实现国土空间可持续利用与保护具有重要意义。以京津冀地区为例,揭示了其国土空间多功能时空变化特征,利用Spearman相关性分析、均方根误差和地理探测器诊断了多功能之间相互关系与权衡强度,并探析了多功能权衡强度影响机制。结果表明,生产功能和生活功能主要集中在东南部平原区,生态功能主要集中在西北山区,2000-2020年生产功能和生活功能提升而生态功能呈退化态势。国土空间多功能权衡强度均值表现为"生活功能-生态功能"＞"生产功能-生态功能"＞"生产功能-生活功能"。2000-2020年生产与生活功能间的权衡强度增强,从0.038上升至0.060;而生产与生态功能间权衡强度减弱,从0.190下降至0.180;生活与生态功能间的权衡强度轻微减弱,从0.206下降至0.205。京津冀西北区是生产与生态功能以及生活与生态功能权衡强度高值区,集中在承德、秦皇岛和北京市。东南部平原区是生产与生活功能权衡强度高值区,尤其是衡水、邯郸和邢台等地权衡明显加剧。国土空间多功能权衡强度空间分异受土地利用、自然因素和社会经济因素共同影响,其中土地利用强度是最主要影响因子,各影响因素在不同年份影响程度略有不同。研究结果可以帮助决策者将国土空间多功能权衡理念纳入国土空间规划与管理。     

Confidence bands for cumulative incidence curves under the additive risk model

In the context of competing risks, the cumulative incidence function is often used to summarize the cause-specific failure-time data. As an alternative to the proportional hazards model, the additive risk model is used to investigate covariate effects by specifying that the subject-specific hazard function is the sum of a baseline hazard function and a regression function of covariates. Based on such a formulation, we present an approach to constructing simultaneous confidence intervals for the cause-specific cumulative incidence function of patients with given risk factors. A melanoma data set is used for the purpose of illustration.     

Contralateral Masking in Bilateral Cochlear Implant Patients: A Model of Medial Olivocochlear Function Loss

Contralateral masking is the phenomenon where a masker presented to one ear affects the ability to detect a signal in the opposite ear. For normal hearing listeners, contralateral masking results in masking patterns that are both sharper and dramatically smaller in magnitude than ipsilateral masking. The goal of this study was to investigate whether medial olivocochlear (MOC) efferents are needed for the sharpness and relatively small magnitude of the contralateral masking function. To do this, bilateral cochlear implant patients were tested because, by directly stimulating the auditory nerve, cochlear implants circumvent the effects of the MOC efferents. The results indicated that, as with normal hearing listeners, the contralateral masking function was sharper than the ipsilateral masking function. However, although there was a reduction in the magnitude of the contralateral masking function compared to the ipsilateral masking function, it was relatively modest. This is in sharp contrast to the results of normal hearing listeners where the magnitude of the contralateral masking function is greatly reduced. These results suggest that MOC function may not play a large role in the sharpness of the contralateral masking function but may play a considerable role in the magnitude of the contralateral masking function.     

KIDNEY FUNCTION TESTS IN CHILDREN

Total renal function is best determined by urinalysis and serum creatinine determination. This may be supplemented, under controlled conditions, by fractional urinary phenosulfonphthalein clearance. The excretory urogram, while invaluable as a diagnostic test, lacks quantitative value as a function test.Until recently, individual renal function determinations depended upon the difficult and tedious cystoscopy and bilateral ureteral catheterization and skilled laboratory techniques. Frequently the necessity of anesthesia artificially depressed kidney function.Since 1956, the radioisotope kidney function test has offered an external, innocuous means of assessing individual renal blood flow, function and drainage plus evaluation of vesico-ureteral reflux. The method has distinct advantages for evaluation of pediatric urological problems.     

Plant Viability as a Function of Temperature Stress (The Richards Function Applied to Data from Freezing Tests of Growing Shoots)

Frost resistance of growing Salix viminalis L. shoots was determined by rating mortality percentage under two commonly used freezing conditions: a condition in which plants were encased in crushed ice and another in which plants were moistened with tap water prior to freezing. The mortality-temperature data were fitted with a logistic function (having a fixed inflection point halfway between the asymptotes) and with a Richards function, which is a double asymptotic sigmoid function with a variable inflection point. Different frost resistance curves were obtained, depending on the freezing conditions used. However, conditions were inadequate for efficient ice nucleation under either condition. This implies that the applied freezing conditions are not suitable when the purpose is to induce and duplicate early ice crystal formation conditions. The Richards derivatives were negatively skewed in the one case and positively skewed in the other case, giving inflection points, as a function of the upper asymptote, situated at 0.37 when shoots were frosted in the presence of ice and at 0.81 when shoots were frozen in the presence of added moisture. These values differed significantly from 0.50, through which the logistic function would have forced the curves. Because of the significant asymmetry in these frost-resistance curves, the Richards function led to a more accurate reflection of the temperature-mortality course of growing Salix stems than the logistic function. The Richards function possesses the flexibility needed to describe plant injury response in terms of physical and plant physiological mechanisms. Therefore, the Richards function is recommended rather than the logistic function for the assessment of frost resistance.     

Late gene function in bacteriophage T4 in the absence of phage DNA replication

Under certain conditions the late genes of coliphage T4 may function in the absence of phage DNA replication. Quasi-late gene function is the function of certain late genes in the absence of both phage DNA replication and the product of the maturation gene 55. It does not depend on how phage DNA synthesis is prevented. Replication-uncoupled late gene function is late gene function from unreplicated DNA in the absence of phage ligase, and is still under the control of gene 55. It is most efficient if phage DNA replication is prevented by a mutation in the phage gene (43) for DNA polymerase. Both quasi-late gene function and replication-uncoupled late gene function are enhanced by the presence of mutations controlling a phage exonuclease (gene 46 or 47).     

应激的光生物调节作用

功能内稳态( function-specific homeostasis,FSH)是维持生物功能充分稳定发挥的负反馈机制,FSH的品质由功能复杂性和稳定性构成.应激打破FSH,处于应激内稳态(stress-specific homeostasis,StSH)的应激称为成功应激,后者能够实现FSH的升级或降级.低水平激光...     

Sequential search and the influence of male quality on female mating decisions

 The patterns of phenotypic association between mated males and females depend on the decision rules that individuals employ during search for a mate. We generalize the sequential search rule and examine how the shape of the function that relates a male character to the benefit of a mating decision influences the threshold value of the male trait that induces females to terminate search. If the fitness function is linear the optimal threshold value of a male character increases with the slope of the function. The phenotypic threshold criterion declines, all else being equal, if the fitness function is made more concave (or less convex) by an increase of the risk of the function. The expression of the trait in females has no effect on the optimal threshold value of a male character if the fitness function is linear and phenotypic values combine additively to influence the benefit of a mating decision; the phenotypic threshold criterion is ubiquitous among females. A convex fitness function induces females with high trait values to adopt a relatively high phenotypic threshold criterion, whereas a concave fitness function induces such females to adopt a low threshold value for the male trait. Thus, linear, convex and concave fitness functions effect random, assortative and disassortative combinations of phenotypes among mated individuals, respectively. Changes of female search behavior induced by changes of the distribution of a male character similarly depend on the shape of the fitness function. A variance-preserving increase of male trait values produces a relatively small increase of the threshold criterion for the male character if the fitness function is concave, relative to conditions in which the fitness function is either linear or convex. Our results suggest that a sequential search rule can in principle induce the kinds of mating patterns observed in nature and that the phenotypic association between mated individuals is likely to depend on how a male character translates into fitness, the distribution of the trait among males and attributes of searching females. Received: 20 September 1997 / Revised version: 13 August 1998     

Demography in stochastic environments. I. Exact distributions of age structure

The steady state distribution of age structure is studied for populations with two age classes and stochastic vital rates. For a serially uncorrelated dichotomic vital rate the distribution of age structure is found analytically to be a singular steplike function; outside a specific region of vital rate values the singular function crosses a threshold to a smooth function. For a vital rate following a correlated two state Markov process the joint distributions of age structure and environment are found analytically to be singular steplike functions; again a threshold marks a transition to a smooth function. For fecundities which are serially uncorrelated but continuously distributed the age structure distribution is obtained as a smooth analytic function for all parameter values. These explicit results have applications to studies of age structure and average growth rate.     

Sequential analysis of surfactant,lung function and inflammation in cystic fibrosis patients

Background

In a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time.

Methods

As part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV₁ 94% of predicted) at three times over a three year period.

Results

There was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV₁, MEF_75/25%VC, and MEF_25%VC. The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period.

Conclusion

Our findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease.     

Small molecule approach to studying protein tyrosine phosphatase

Understanding the function of protein tyrosine phosphatases (PTPs) is crucial to deciphering cellular signaling in higher organisms. Of the 100 putative PTPs in human genome, only a little is known about their precise biological functions. Thus establishing novel ways to study PTP function remains a top priority among researchers. Classical genetics and more recently the use of RNA interference (RNAi) for gene silencing remains a popular choice to study function. However, the one gene-one function hypothesis is now recognized as an oversimplified scenario, especially among the signaling proteins such as PTPs. Therefore, there is a need to understand gene function in an appropriate cellular context. Since proteins are the work horses of the cell, alteration of protein function by various means is a particularly attractive strategy. In this context, the chemical approach, where a small molecule is used to affect the function of the desired protein is increasingly being recognized as a method of choice. In this review, we describe how small molecules can be used to study the function of a prototypical PTP, PTP1B, which is a negative regulator in insulin signaling. This includes our initial strategies for finding the most potent and specific PTP1B inhibitor to date, synthesizing cell permeable analogues suitable for cellular studies, and using them to dissect the role of PTP1B in the insulin signaling pathway. This approach is potentially general and thus could be utilized to study the function of other PTPs.