Cyclic AMP/GMP-dependent modulation of Ca2+ channels sets the polarity of nerve growth-cone turning

Signalling by intracellular second messengers such as cyclic nucleotides and Ca2+ is known to regulate attractive and repulsive guidance of axons by extracellular factors. However, the mechanism of interaction among these second messengers in determining the polarity of the guidance response is largely unknown. Here, we report that the ratio of cyclic AMP to cyclic GMP activities sets the polarity of netrin-1-induced axon guidance: high ratios favour attraction, whereas low ratios favour repulsion. Whole-cell recordings of Ca2+ currents at Xenopus spinal neuron growth cones indicate that cyclic nucleotide signalling directly modulates the activity of L-type Ca2+ channels (LCCs) in axonal growth cones. Furthermore, cGMP signalling activated by an arachidonate 12-lipoxygenase metabolite suppresses LCC activity triggered by netrin-1, and is required for growth-cone repulsion mediated by the DCC-UNC5 receptor complex. By linking cAMP and cGMP signalling and modulation of Ca2+ channel activity in growth cones, these findings delineate an early membrane-associated event responsible for signal transduction during bi-directional axon guidance.     

A mouse model for spinal muscular atrophy

The survival motor neuron gene is present in humans in a telomeric copy, SMN1, and several centromeric copies, SMN2. Homozygous mutation of SMN1 is associated with proximal spinal muscular atrophy (SMA), a severe motor neuron disease characterized by early childhood onset of progressive muscle weakness. To understand the functional role of SMN1 in SMA, we produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2. Smn-/- mice died during the peri-implantation stage. In contrast, transgenic mice harbouring SMN2 in the Smn-/- background showed pathological changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathological changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. Our results demonstrate that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn-/-SMN2 mice reflect those seen in SMA patients, providing a mouse model for this disease.     

一个分子序列的进化模型

本文提出了关于分子序列进化的一个简单模型,序列由于随机的点突变和一定的选择规则作用而不断变化,利用这个模型,可以解释进化中信息参数的下降,和的上升,并可解释序列具有短程的关联长度,对不同物种的出现,也可作初步讨论。     

A Meta‐learning Framework for Bankruptcy Prediction

The implication of corporate bankruptcy prediction is important to financial institutions when making lending decisions. In related studies, many bankruptcy prediction models have been developed based on some machine‐learning techniques. This paper presents a meta‐learning framework, which is composed of two‐level classifiers for bankruptcy prediction. The first‐level multiple classifiers perform the data reduction task by filtering out unrepresentative training data. Then, the outputs of the first‐level classifiers are utilized to create the second‐level single (meta) classifier. The experiments are based on five related datasets and the results show that the proposed meta‐learning framework provides higher prediction accuracy rates and lower type I/II errors when compared with the stacked generalization classifier and other three widely developed baselines, such as neural networks, decision trees, and logistic regression. Copyright © 2011 John Wiley & Sons, Ltd.     

Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder

Removal of toxic substances from the blood depends on patent connections between the kidney, ureters and bladder that are established when the ureter is transposed from its original insertion site in the male genital tract to the bladder. This transposition is thought to occur as the trigone forms from the common nephric duct and incorporates into the bladder. Here we re-examine this model in the context of normal and abnormal development. We show that the common nephric duct does not differentiate into the trigone but instead undergoes apoptosis, a crucial step for ureter transposition controlled by vitamin A-induced signals from the primitive bladder. Ureter abnormalities occur in 1-2% of the human population and can cause obstruction and end-stage renal disease. These studies provide an explanation for ureter defects underlying some forms of obstruction in humans and redefine the current model of ureter maturation.     

A hybrid model of knowledge management for new service development

Although many theories regarding the implementation of knowledge management (KM) in organizations have been proposed and studied, most applications tend to stand alone without incorporating the business processes. Different categories of knowledge provide different benefits and how to integrate various categories of KM into a hybrid approach as an effective KM manner remains strategically important, and yet is still understudied. Therefore, in this paper a hybrid model that integrates principal KM applications for new service development (NSD) and the measurement of the resulting financial benefits have been developed. The proposed KM model incorporates newsgroups, knowledge forums, knowledge asset management and knowledge application processes as a hybrid means for sharing organizational knowledge along two axes, explicit vs. implicit and individual vs. collective. One of the largest management consulting companies in Taiwan, China, whose process model of NSD was standing alone with KM applications, was selected for the case study. A set of hybrid KM processes was developed to implement the proposed KM model, and it illustrates an application with greater financial benefits for integrating hybrid KM practices into the business process. Based on knowledge value added (KVA) validation, the proposed KM model provides a new operating system for sharing NSD knowledge within an organization. Through the case study by measuring the achieved financial results, the proposed KM model is found to provide an exclusive hybrid platform with an empirical process model to address innovative approaches and practical values of KM within an organization.     

Estimation of Generalized DINA Model with Order Restrictions

Cognitive diagnostic models provide valuable information on whether a student has mastered each of the attributes a test intends to evaluate. Despite its generality, the generalized DINA model allows for the possibility of lower correct rates for students who master more attributes than those who know less. This paper considers the use of order-constrained parameter space of the G-DINA model to avoid such a counter-intuitive phenomenon and proposes two algorithms, the upward and downward methods, for parameter estimation. Through simulation studies, we compare the accuracy in parameter estimation and in classification of attribute patterns obtained from the proposed two algorithms and the current approach when the restricted parameter space is true. Our results show that the upward method performs the best among the three, and therefore it is recommended for estimation, regardless of the distribution of respondents’ attribute patterns, types of test items, and the sample size of the data.     

TRIM24 links a non-canonical histone signature to breast cancer

Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.