A Robust GWSS Method to Simultaneously Detect Rare and Common Variants for Complex Disease

The rapid advances in sequencing technologies and the resulting next-generation sequencing data provide the opportunity to detect disease-associated variants with a better solution, in particular for low-frequency variants. Although both common and rare variants might exert their independent effects on the risk for the trait of interest, previous methods to detect the association effects rarely consider them simultaneously. We proposed a class of test statistics, the generalized weighted-sum statistic (GWSS), to detect disease associations in the presence of common and rare variants with a case-control study design. Information of rare variants was aggregated using a weighted sum method, while signal directions and strength of the variants were considered at the same time. Permutations were performed to obtain the empirical p-values of the test statistics. Our simulation showed that, compared to the existing methods, the GWSS method had better performance in most of the scenarios. The GWSS (in particular VDWSS-t) method is particularly robust for opposite association directions, association strength, and varying distributions of minor-allele frequencies. It is therefore promising for detecting disease-associated loci. For empirical data application, we also applied our GWSS method to the Genetic Analysis Workshop 17 data, and the results were consistent with the simulation, suggesting good performance of our method. As re-sequencing studies become more popular to identify putative disease loci, we recommend the use of this newly developed GWSS to detect associations with both common and rare variants.     

植物抗病信号转导途径

植物抗病信号转导途径的研究一直是植物病理学关注的热点,近年来国内外不少实验室正在大量分离与植物抗病有关的突变体,克隆与抗病调节有关的基因并研究其功能。实验表明,一些植物抗病信号途径中的正、负调节因子及不同信号转导途径之间形成复杂的调控网络。在着重对R基因介导的抗病信号途径、细胞程序化死亡、水杨酸信号途径、茉莉酸和乙烯信号途径和诱导系统抗性途径研究进展加以综述的同时,对各抗病信号途径之间信号交换的复杂性进行了讨论。     

Resonant Drift of Spiral Waves in the Complex Ginzburg-Landau Equation

Weak periodic external perturbations of an autowave medium can cause large-distance directed motion of the spiral wave. This happens when the period of the perturbation coincides with, or is close to the rotation period of a spiral wave, or its multiple. Such motion is called resonant or parametric drift. It may be used for low-voltage defibrillation of heart tissue. Theory of the resonant drift exists, but so far was used only qualitatively. In this paper, we show good quantitative agreement of the theory with direct numerical simulations. This is done for Complex Ginzburg-Landau Equation, one of the simplest autowave models.     

Neuroinflammatory Signaling Upregulation in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive, neurodestructive process of the human neocortex, characterized by the deterioration of memory and higher cognitive function. A progressive and irreversible brain disorder, AD is characterized by three major pathogenic episodes involving (a) an aberrant processing and deposition of beta-amyloid precursor protein (betaAPP) to form neurotoxic beta-amyloid (betaA) peptides and an aggregated insoluble polymer of betaA that forms the senile plaque, (b) the establishment of intraneuronal neuritic tau pathology yielding widespread deposits of agyrophilic neurofibrillary tangles (NFT) and (c) the initiation and proliferation of a brain-specific inflammatory response. These three seemingly disperse attributes of AD etiopathogenesis are linked by the fact that proinflammatory microglia, reactive astrocytes and their associated cytokines and chemokines are associated with the biology of the microtubule associated protein tau, betaA speciation and aggregation. Missense mutations in the presenilin genes PS1 and PS2, implicated in early onset familial AD, cause abnormal betaAPP processing with resultant overproduction of betaA42 and related neurotoxic peptides. Specific betaA fragments such as betaA42 can further potentiate proinflammatory mechanisms. Expression of the inducible oxidoreductase cyclooxygenase-2 and cytosolic phospholipase A2 (cPLA2) are strongly activated during cerebral ischemia and trauma, epilepsy and AD, indicating the induction of proinflammatory gene pathways as a response to brain injury. Neurotoxic metals such as aluminum and zinc, both implicated in AD etiopathogenesis, and arachidonic acid, a major metabolite of brain cPLA2 activity, each polymerize hyperphosphorylated tau to form NFT-like bundles. Further, epidemiological and longitudinal studies have identified a reduced risk for AD in patients (<70 yrs) previously treated with non-steroidal anti-inflammatory drugs for non-CNS afflictions that include arthritis. This review will focus on the interrelationships between the mechanisms of PS1, PS2 and betaAPP gene expression, tau and betaA deposition and the induction, regulation and proliferation in AD of the neuroinflammatory response. Novel therapeutic interventions in AD are discussed.     

Studies on Pantoea citrea, the Causal Agent of Pink Disease of Pineapple

The causal agent of pink disease of pineapple has been identified as Pantoea citrea, a member of the Enterobacteriaceae. Comparative physiological and biochemical analyses demonstrated that P. citrea isolated from diseased pineapple fruit in the Philippines possesses features identical to those of an American Type Culture Collection type strain of P. citrea and not to those of P. ananas, P. herbicola (formerly Erwinia herbicola), and P. stewartii (formerly Erwinia stewartii). P. citrea induces the production of compounds in pineapple which become pink to reddish-brown upon cooking the fruit, pulp, or juice. This distinct colour is not induced by Escherichia coli, Agrobacterium tumefaciens, Burkholderia gladioli, Pseudomonas fluorescens, Gluconobacter oxydans, Acetobacter aceti, and Acinetobacter calcoaceticus. Like other well characterized bacteria pathogens, such as Pseudomonas syringae pv. phaseolicola, P. citrea elicits the hypersensitive response (HR) in tobacco. By contrast, G. oxydans and A. aceti that have been previously implicated as the causal agents of pink disease, do not elicit HR. Although the nature of the pink colour in pineapple produced by P. citrea has not been elucidated, the locus conferring this activity has been located on its chromosome. The pink colour can be restored in an avirulent, pink colour defective mutant strain, CMC6, by complementation in trans with a specific 3.8 kb genomic DNA fragment of P. citrea. This suggests that P. citrea contains the genetic elements that are required for pink disease.     

细胞复杂信号转导的调控模式

越来越多的证据表明 ,细胞信号转导途径之间存在着各种各样的相互通讯(ｃｒｏｓｓｔａｌｋ) ,由此形成了复杂的信号转导网络。特定的输入信号在通过这一网络传输信号时 ,信号的强度或 /和时间会被修饰或调控 ,从而引发不同的生理效应[1,2 ] 。通过对细胞信号转导网络的研究 ,能使我们更好的理解信号转导网络改变所引发的病理过程 ,更好的理解肿瘤、糖尿病、精神病等疾病的发病机理。现将存在于复杂细胞信号转导网络中的信号转导调控模式描述如下。1 .双稳调控模式最简单的双稳调控模式由两条相互影响的信号转导途径组成 ,其间存在正反馈循环…     

Cross-Talk between Signaling Pathways Can Generate Robust Oscillations in Calcium and cAMP

Background

To control and manipulate cellular signaling, we need to understand cellular strategies for information transfer, integration, and decision-making. A key feature of signal transduction is the generation of only a few intracellular messengers by many extracellular stimuli.

Methodology/Principal Findings

Here we model molecular cross-talk between two classic second messengers, cyclic AMP (cAMP) and calcium, and show that the dynamical complexity of the response of both messengers increases substantially through their interaction. In our model of a non-excitable cell, both cAMP and calcium concentrations can oscillate. If mutually inhibitory, cross-talk between the two second messengers can increase the range of agonist concentrations for which oscillations occur. If mutually activating, cross-talk decreases the oscillation range, but can generate ‘bursting’ oscillations of calcium and may enable better filtering of noise.

Conclusion

We postulate that this increased dynamical complexity allows the cell to encode more information, particularly if both second messengers encode signals. In their native environments, it is unlikely that cells are exposed to one stimulus at a time, and cross-talk may help generate sufficiently complex responses to allow the cell to discriminate between different combinations and concentrations of extracellular agonists.     

Current Status and Future Directions of Research in Complex Signaling

1 Introduction The term'complex signaling'reflects a recent scientific focus on the multiple elements frequently incorporated into animal signals(reviewed in ...     

Evolution, Causal Biology, and Classification

Brundin, L. (Section of Entomology, Swedish Museum of Natural History, Stockholm, Sweden.) Evolution, causal biology, and classification. Zool. Scripta 1 (3–4): 107–120, 1972.–The pros and cons of different approaches to classification are discussed against the background of a critical survey of the leading principles of evolution and the methodological advices furnished by the nature of the evolutionary process for the attainment of an adequate reference system of causal biology. It is shown that such a system has to be a reconstruction of nature's own hierarchy. The reasons for the present disagreement between the Hennig school and the Simpson-Mayr school are discussed at some length, and it is stressed that the classificatory dilemma of the latter school is an unavoidable consequence of its quantitative approach and hence self-inflicted.     

Species-Specific Detection and Identification of Fusarium Species Complex,the Causal Agent of Sugarcane Pokkah Boeng in China

Background

Pokkah boeng disease caused by the Fusarium species complex results in significant yield losses in sugarcane. Thus, the rapid and accurate detection and identification of the pathogen is urgently required to manage and prevent the spreading of sugarcane pokkah boeng.

Methods

A total of 101 isolates were recovered from the pokkah boeng samples collected from five major sugarcane production areas in China throughout 2012 and 2013. The causal pathogen was identified by morphological observation, pathogenicity test, and phylogenetic analysis based on the fungus-conserved rDNA-ITS. Species-specific TaqMan real-time PCR and conventional PCR methods were developed for rapid and accurate detection of the causal agent of sugarcane pokkah boeng. The specificity and sensitivity of PCR assay were also evaluated on a total of 84 isolates of Fusarium from China and several isolates from other fungal pathogens of Sporisorium scitamineum and Phoma sp. and sugarcane endophyte of Acremonium sp.

Result

Two Fusarium species (F. verticillioides and F. proliferatum) that caused sugarcane pokahh boeng were identified by morphological observation, pathogenicity test, and phylogenetic analysis. Species-specific TaqMan PCR and conventional PCR were designed and optimized to target their rDNA-ITS regions. The sensitivity of the TaqMan PCR was approximately 10 pg of fungal DNA input, which was 1,000-fold over conventional PCR, and successfully detected pokkah boeng in the field-grown sugarcane.

Conclusions/Significance

This study was the first to identify two species, F. verticillioides and F. proliferatum, that were causal pathogens of sugarcane pokkah boeng in China. It also described the development of a species-specific PCR assay to detect and confirm these pathogens in sugarcane plants from mainland China. This method will be very useful for a broad range of research endeavors as well as the regulatory response and management of sugarcane pokkah boeng.