广义Kolmogorov模型的Lyapunov函数构造新算法及其应用

本文对广义Kolmogorov模型,给出构造Lyapunov函数的新算法,在文献1中只对其中某些特殊类型给出几种特殊的构造方法,而本文给出的是这类模型的一般新算法,应用较广泛。     

Temporal organization of feeding in Syrian hamsters with a genetically altered circadian period

The variation in spontaneous meal patterning was studied in three genotypes (tau +/+, tau +/-and tau -/-) of the Syrian hamster with an altered circadian period. Feeding activity was monitored continuously in 13 individuals from each genotype in constant dim light conditions. All three genotypes had on average six feeding episodes during the circadian cycle (about 20h in homozygous tau mutants and 22h in heterozygotes compared with 24h in wild-type hamsters). Thus, homozygous tau mutant hamsters had significantly more feeding episodes per 24h than wild types, and heterozygotes were intermediate. The average duration of feeding bouts (FBs) was indistinguishable (around 30 minutes) among the three genotypes, whereas the intermeal (IM) intervals were significantly shorter for homozygote tau mutant hamsters (99 minutes), intermediate for heterozygotes (116 minutes), and the longest for wild-type hamsters (148 minutes). Thus, the meal-to-meal duration was on average 25% shorter in homozygous tau mutants (16% in heterozygous) than in wild-type hamsters. The reduction of the circadian period has a pronounced effect on short-term feeding rhythms and meal frequency in hamsters carrying the tau mutation. (Chronobiology International, 18(4), 657-664, 2001)     

Analysis of Matched Case–Control Data in Presence of Nonignorable Missing Exposure

Summary.   The present article deals with informative missing (IM) exposure data in matched case–control studies. When the missingness mechanism depends on the unobserved exposure values, modeling the missing data mechanism is inevitable. Therefore, a full likelihood-based approach for handling IM data has been proposed by positing a model for selection probability, and a parametric model for the partially missing exposure variable among the control population along with a disease risk model. We develop an EM algorithm to estimate the model parameters. Three special cases: (a) binary exposure variable, (b) normally distributed exposure variable, and (c) lognormally distributed exposure variable are discussed in detail. The method is illustrated by analyzing a real matched case–control data with missing exposure variable. The performance of the proposed method is evaluated through simulation studies, and the robustness of the proposed method for violation of different types of model assumptions has been considered.     

Pimozide reduces toxic forms of tau in TauC3 mice via 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease‐associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non‐mTOR pathways is a new option for autophagy‐based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK‐Unc‐51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase‐cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40‐insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR‐independent AMPK‐ULK1 axis.     

Conditionally inducible tau mice – designing a better mouse model of neurodegenerative diseases

Neuronal cell death underlies the majority of age-related human neurodegenerative disorders that culminate with salient and severe cognitive decline affecting patients' quality of life, identity and eventually leading to death. The identification of disease-causing genes in familial forms of neurodegenerative diseases enabled the development of genetic models closely replicating pathologies found in human central nervous system. These models dramatically precipitated our understanding of molecular events leading to neuronal death in many neurodegenerative disorders. Today's large range of cellular and animal models generate rapidly accumulating biochemical and neuropathological data on changes induced by mutated or dysfunctional proteins implicated in neuronal loss. Most of these models are complementary, although all have intrinsic limitations as well as specific advantages. Development of conditional transgenic mouse models in which a deleterious effect of a transgene can be regulated in a controlled way created new possibilities of addressing the basic mechanisms of neurodegeneration and provided a new angle for the development and testing of new therapeutic approaches.     

Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain

Previously, we found that amyloid beta-protein (Abeta)1-42 exhibits neurotoxicity, while Abeta1-40 serves as an antioxidant molecule by quenching metal ions and inhibiting metal-mediated oxygen radical generation. Here, we show another neuroprotective action of nonamyloidogenic Abeta1-40 against Abeta1-42-induced neurotoxicity in culture and in vivo. Neuronal death was induced by Abeta1-42 at concentrations higher than 2 microm, which was prevented by concurrent treatment with Abeta1-40 in a dose-dependent manner. However, metal chelators did not prevent Abeta1-42-induced neuronal death. Circular dichroism spectroscopy showed that Abeta1-40 inhibited the beta-sheet transformation of Abeta1-42. Thioflavin-T assay and electron microscopy analysis revealed that Abeta1-40 inhibited the fibril formation of Abeta1-42. In contrast, Abeta1-16, Abeta25-35, and Abeta40-1 did not inhibit the fibril formation of Abeta1-42 nor prevent Abeta1-42-induced neuronal death. Abeta1-42 injection into the rat entorhinal cortex (EC) caused the hyperphosphorylation of tau on both sides of EC and hippocampus and increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the ipsilateral EC, which were prevented by the concurrent injection of Abeta1-40. These results indicate that Abeta1-40 protects neurons from Abeta1-42-induced neuronal damage in vitro and in vivo, not by sequestrating metals, but by inhibiting the beta-sheet transformation and fibril formation of Abeta1-42. Our data suggest a mechanism by which elevated Abeta1-42/Abeta1-40 ratio accelerates the development of Alzheimer's disease (AD) in familial AD.     

Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain

Of 21 phosphorylation sites identified in PHF-tau 11 are on ser/thr-X motifs and are probably phosphorylated by non-proline-dependent protein kinases (non-PDPKs). The identities of the non-PDPKs and how they interact to hyperphosphorylate PHF-tau are still unclear. In a previous study we have shown that the rate of phosphorylation of human tau 39 by a PDPK (GSK-3) was increased several fold if tau were first prephosphorylated by non-PDPKs (Singh et al., FEBS Lett 358: 267-272, 1995). In this study we have examined how the specificity of a non-PDPK for different sites on human tau 39 is modulated when tau is prephosphorylated by other non-PDPKs (A-kinase, C-kinase, CK-1, CaM kinase II) as well as a PDPK (GSK-3). We found that the rate of phosphorylation of tau 39 by a non-PDPK can be stimulated if tau were first prephosphorylated by other non-PDPKs. Of the four non-PDPKs only CK-1 can phosphorylate sites (thr 231, ser 396, ser 404) known to be present in PHF-tau. Further, these sites were phosphorylated more rapidly and to a greater extent by CK-1 if tau 39 were first prephosphorylated by A-kinase, CaM kinase II or GSK-3. These results suggest that the site specificities of the non-PDPKs that participate in PHF-tau hyperphosphorylation can be modulated at the substrate level by the phosphorylation state of tau.Abbreviations PHF paired helical filaments - A-kinase cyclic AMP-dependent protein kinase - CaM kinase II calcium/calmodulin-dependent protein kinase II - C-kinase calcium/phospholipid-dependent protein kinase - CK-1 casein kinase-1 - CK-2 casein kinase-2 - GSK-3 glycogen synthase kinase-3 - MAP kinase mitogen-activated protein kinase - PDPK proline-dependent protein kinase     

A semiparametric empirical likelihood method for biased sampling schemes with auxiliary covariates

We consider a semiparametric inference procedure for data from epidemiologic studies conducted with a two-component sampling scheme where both a simple random sample and multiple outcome- or outcome-/auxiliary-dependent samples are observed. This sampling scheme allows the investigators to oversample certain subpopulations believed to have more information about the regression model while still gaining insights about the underlying population through the simple random sample. We focus on settings where there is no additional information about the parent cohort and the sampling probability is nonidentifiable. We motivate our problem with an ongoing study to assess the association between the mutation level of epidermal growth factor receptor (EGFR) and the antitumor response to EGFR-targeted therapy among nonsmall cell lung cancer patients. The proposed method applies to both binary and multicategorical outcome data and allows an arbitrary link function in the framework of generalized linear models. Simulation studies show that the proposed estimator has nice small sample properties. The proposed method is illustrated with a data example.     

Inference methods for the conditional logistic regression model with longitudinal data

This paper considers inference methods for case-control logistic regression in longitudinal setups. The motivation is provided by an analysis of plains bison spatial location as a function of habitat heterogeneity. The sampling is done according to a longitudinal matched case-control design in which, at certain time points, exactly one case, the actual location of an animal, is matched to a number of controls, the alternative locations that could have been reached. We develop inference methods for the conditional logistic regression model in this setup, which can be formulated within a generalized estimating equation (GEE) framework. This permits the use of statistical techniques developed for GEE-based inference, such as robust variance estimators and model selection criteria adapted for non-independent data. The performance of the methods is investigated in a simulation study and illustrated with the bison data analysis.     

延河流域本氏针茅(Stipa bungeana)分布预测——广义相加模型及其应用

物种分布预测,对于物种的保护、利用和恢复具有重要意义.利用广义相加模型(GAM,Generalized Additive Model),对延河流域典型地带性物种本氏针茅(Stipa bungeana)的空间分布预测进行研究,以期为该流域本氏针茅草地的保护、恢复等提供依据.结果表明,本氏针茅分布的环境梯度较广,在坡度、坡向、温度与降雨的各个梯度上都有分布,除高平地和侵蚀剧烈的沟道外,各种地形部位上亦可以存在.建立的广义相加模型表明,本氏针茅的分布主要取决于年均蒸发量和温度季节变化两个因子,而非单纯的降雨、温度因素.从其分布概率看,本氏针茅在延河流域大部分地区都有可能分布,但其分布集中区主要在中北部,与实际观测相符.模型检验表明,建立的模型满足统计要求.