Low-rank scale-invariant tensor product smooths for generalized additive mixed models

A general method for constructing low-rank tensor product smooths for use as components of generalized additive models or generalized additive mixed models is presented. A penalized regression approach is adopted in which tensor product smooths of several variables are constructed from smooths of each variable separately, these "marginal" smooths being represented using a low-rank basis with an associated quadratic wiggliness penalty. The smooths offer several advantages: (i) they have one wiggliness penalty per covariate and are hence invariant to linear rescaling of covariates, making them useful when there is no "natural" way to scale covariates relative to each other; (ii) they have a useful tuneable range of smoothness, unlike single-penalty tensor product smooths that are scale invariant; (iii) the relatively low rank of the smooths means that they are computationally efficient; (iv) the penalties on the smooths are easily interpretable in terms of function shape; (v) the smooths can be generated completely automatically from any marginal smoothing bases and associated quadratic penalties, giving the modeler considerable flexibility to choose the basis penalty combination most appropriate to each modeling task; and (vi) the smooths can easily be written as components of a standard linear or generalized linear mixed model, allowing them to be used as components of the rich family of such models implemented in standard software, and to take advantage of the efficient and stable computational methods that have been developed for such models. A small simulation study shows that the methods can compare favorably with recently developed smoothing spline ANOVA methods.     

Estimating effects of a single gene and polygenes on quantitative traits from a diallel design

A genetic model is developed with additive and dominance effects of a single gene and polygenes as well as general and specific reciprocal effects for the progeny from a diallel mating design. The methods of ANOVA, minimum norm quadratic unbiased estimation (MINQUE), restricted maximum likelihood estimation (REML), and maximum likelihood estimation (ML) are suggested for estimating variance components, and the methods of generalized least squares (GLS) and ordinary least squares (OLS) for fixed effects, while best linear unbiased prediction, linear unbiased prediction (LUP), and adjusted unbiased prediction are suggested for analyzing random effects. Monte Carlo simulations were conducted to evaluate the unbiasedness and efficiency of statistical methods involving two diallel designs with commonly used sample sizes, 6 and 8 parents, with no and missing crosses, respectively. Simulation results show that GLS and OLS are almost equally efficient for estimation of fixed effects, while MINQUE (1) and REML are better estimators of the variance components and LUP is most practical method for prediction of random effects. Data from a Drosophila melanogaster experiment (Gilbert 1985a, Theor appl Genet 69:625–629) were used as a working example to demonstrate the statistical analysis. The new methodology is also applicable to screening candidate gene(s) and to other mating designs with multiple parents, such as nested (NC Design I) and factorial (NC Design II) designs. Moreover, this methodology can serve as a guide to develop new methods for detecting indiscernible major genes and mapping quantitative trait loci based on mixture distribution theory. The computer program for the methods suggested in this article is freely available from the authors.     

Cell imaging and manipulation by nonlinear optical microscopy

Advances in the technologies for labeling and imaging biological samples drive a constant progress in our capability of studying structures and their dynamics within cells and tissues. In the last decade, the development of numerous nonlinear optical microscopies has led to a new prospective both in basic research and in the potential development of very powerful noninvasive diagnostic tools. These techniques offer large advantages over conventional linear microscopy with regard to penetration depth, spatial resolution, three-dimensional optical sectioning, and lower photobleaching. Additionally, some of these techniques offer the opportunity for optically probing biological functions directly in living cells, as highlighted, for example, by the application of second-harmonic generation to the optical measurement of electrical potential and activity in excitable cells. In parallel with imaging techniques, nonlinear microscopy has been developed into a new area for the selective disruption and manipulation of intracellular structures, providing an extremely useful tool of investigation in cell biology. In this review we present some basic features of nonlinear microscopy with regard both to imaging and manipulation, and show some examples to illustrate the advantages offered by these novel methodologies.     

YajL, prokaryotic homolog of parkinsonism-associated protein DJ-1, functions as a covalent chaperone for thiol proteome

YajL is the closest Escherichia coli homolog of the Parkinsonism-associated protein DJ-1, a multifunctional oxidative stress response protein whose biochemical function remains unclear. We recently reported the aggregation of proteins in a yajL mutant in an oxidative stress-dependent manner and that YajL exhibits chaperone activity. Here, we show that YajL displays covalent chaperone and weak protein oxidoreductase activities that are dependent on its exposed cysteine 106. It catalyzes reduced RNase oxidation and scrambled RNase isomerization and insulin reduction and forms mixed disulfides with many cellular proteins upon oxidative stress. The formation of mixed disulfides was detected by immunoblotting bacterial extracts with anti-YajL antibodies under nonreducing conditions. Disulfides were purified from bacterial extracts on a YajL affinity column, separated by nonreducing-reducing SDS-PAGE, and identified by mass spectrometry. Covalent YajL substrates included ribosomal proteins, aminoacyl-tRNA synthetases, chaperones, catalases, peroxidases, and other proteins containing cysteines essential for catalysis or FeS cluster binding, such as glyceraldehyde-3-phosphate dehydrogenase, aldehyde dehydrogenase, aconitase, and FeS cluster-containing subunits of respiratory chains. In addition, we show that DJ-1 also forms mixed disulfides with cytoplasmic proteins upon oxidative stress. These results shed light on the oxidative stress-dependent chaperone function of YajL and identify YajL substrates involved in translation, stress protection, protein solubilization, and metabolism. They reveal a crucial role for cysteine 106 and suggest that DJ-1 also functions as a covalent chaperone. These findings are consistent with several defects observed in yajL or DJ-1 mutants, including translational defects, protein aggregation, oxidative stress sensitivity, and metabolic deficiencies.     

Ca<Superscript>2+</Superscript> channel currents of cortical neurons from pure and mixed cultures

Voltage-gated Ca²⁺ channels (VGCCs) are key regulators of many neuronal functions, and involved in multiple central nervous system diseases. In the last 30 years, a large number of injury and disease models have been established based on cultured neurons. Culture with serum develops a mixture of neurons and glial cells, while culture without serum develops pure neurons. Both of these neuronal-culture methods are widely used. However, the properties of Ca²⁺ currents in neurons from these two cultures have not been compared. In this study, we cultured rat cortical neurons in serum-containing or -free medium and then recorded the Ca²⁺ channel currents using patch-clamp technique. Our results showed that there were significant differences in the amplitude and activation properties of whole-cell Ca²⁺ channel currents, and of non-L-type Ca²⁺ channel currents between the neurons from these two culture systems. Our data suggested that the difference of whole-cell Ca²⁺ currents may result from the differences in non-L-type currents. Understanding of these properties will considerably advance studies of VGCCs in neurons from pure or mixed culture.     

Global asymptotic stability of density dependent integral population projection models

Many stage-structured density dependent populations with a continuum of stages can be naturally modeled using nonlinear integral projection models. In this paper, we study a trichotomy of global stability result for a class of density dependent systems which include a Platte thistle model. Specifically, we identify those systems parameters for which zero is globally asymptotically stable, parameters for which there is a positive asymptotically stable equilibrium, and parameters for which there is no asymptotically stable equilibrium.     

Gap junctions modulate seizures in a mean-field model of general anesthesia for the cortex

During slow-wave sleep, general anesthesia, and generalized seizures, there is an absence of consciousness. These states are characterized by low-frequency large-amplitude traveling waves in scalp electroencephalogram. Therefore the oscillatory state might be an indication of failure to form coherent neuronal assemblies necessary for consciousness. A generalized seizure event is a pathological brain state that is the clearest manifestation of waves of synchronized neuronal activity. Since gap junctions provide a direct electrical connection between adjoining neurons, thus enhancing synchronous behavior, reducing gap-junction conductance should suppress seizures; however there is no clear experimental evidence for this. Here we report theoretical predictions for a physiologically-based cortical model that describes the general anesthetic phase transition from consciousness to coma, and includes both chemical synaptic and direct electrotonic synapses. The model dynamics exhibits both Hopf (temporal) and Turing (spatial) instabilities; the Hopf instability corresponds to the slow (≲8 Hz) oscillatory states similar to those seen in slow-wave sleep, general anesthesia, and seizures. We argue that a delicately balanced interplay between Hopf and Turing modes provides a canonical mechanism for the default non-cognitive rest state of the brain. We show that the Turing mode, set by gap-junction diffusion, is generally protective against entering oscillatory modes; and that weakening the Turing mode by reducing gap conduction can release an uncontrolled Hopf oscillation and hence an increased propensity for seizure and simultaneously an increased sensitivity to GABAergic anesthesia.     

Phenotypic diversity and epigenomic variation - The utility of mass spectrometric analysis of DNA methylation

Epigenomic variation may underlie phenotypic diversity that is not attributable to differences in genomic sequence. Such processes provide an organism the flexibility to respond to changing environmental cues within its lifetime, and perhaps its offspring's lifetime, and would therefore be expected to confer a selective advantage in evolutionary terms. Analysis of epigenomic variation within a population may be both a useful measure of developmental exposures and an indicator of future phenotype. A key molecular indicator of epigenomic variation in organisms is the chemical modification of DNA by methylation at specific nucleotide residues in the genome. Here we discuss how mass spectrometry can be utilised to provide quantitative analysis of DNA methylation patterns across populations. This article is part of a Special Section entitled: Understanding genome regulation and genetic diversity by mass spectrometry.     

一种基于Wilson-Cowan双节点耦合振子模型的图像增强方法

针对模拟大脑节律现象的Wilson-Cowan双节点耦合振子模型,选取满足该模型产生极限环振荡条件的参数,采用连续灰度阶图像块作为输入,兴奋性亚群节点响应作为图像增强的输出,做出刺激响应曲线,发现该曲线与图像处理领域中用于图像增强的Gamma校正曲线相似,说明Wilson-Cowan双节点耦合振子模型可以作为一种新的图像增强方法,同时也为基于Gamma校正曲线的图像增强提供了一种神经机制。将新方法与Retinex算法做对比,表现出了更好的图像增强性能。     

含不可忽略缺失数据非线性再生散度模型参数的Bayes估计

给出协变量带有不可忽略缺失数据的非线性再生散度模型的Bayes方法,缺失数据机制由Logistic回归模型来确定.Gibbs抽样技术和Metropolis-Hastings算法(简称MH算法)用来得到模型参数、缺失数据机制中回归系数的联合Bayes估计,并用实例加以说明.