We have in particular focused our study on the spacer extension in order to tune the intramolecular TTF···TTF distance within the clip and, consequently, the redox behavior of the receptor. Carried out at different concentrations in solution, electrochemical and spectroelectrochemical experiments provide evidence of mixed-valence and/or π-dimer intermolecular interactions between TTF units from two closed clips. The stepwise oxidation of each molecular clip involves an electrochemical mechanism with three one-electron processes and two charge-coupled chemical reactions, a scheme which is supported by electrochemical simulations. The fine-tunable π-donating ability of the TTF units and the cavity size allow to control binding interaction towards a strong electron acceptor such as tetrafluorotetracyanoquinodimethane (F Thanks to its remarkable redox properties and strong π-donating character demonstrated with the pioneering work of F. Wudl in the early 1970s –5. In adMolecular clips and tweezers can be defined as receptors presenting an open cavity composed of two interaction sites which are separated by a spacer –15. Idea1–4 + mixed-valence dimer [+)2 π-dimer [In agreement with the simulated concentration–time profiles in thin layer conditions  – bottomce dimer –48 and t π-dimer . The ban2]+˙ mixed-valence dimer and/or (TTF+˙)2 dimer species concerned systems for which the dimer stabilization is resulting from the close proximity of the two TTF units. That is the case for conjugated bisTTF systems +˙ mixed-valence dimer and/or (TTF+˙)2 dimer species but their self-association organization could not be yet demonstrated. The presence of more or less sterically bulky groups at the periphery of the TTF moieties does not provide an advantage for the self-assembly of dimers. Moreover, this dimerization phenomenon which is driven by the inclusion of one sidewall into the cavity of the opposing clip is not observed in the solid state for clips 2 and 3  were determined between two clips in the solid state.By comparison with these results observed for molecular clip 15 , it is c 2 and 3 . This ty3 and 4 for this study. Molecular clip 3 presents better π-donating ability according to CV study and a smaller interplanar TTF distance . Binding properties were studied using 1,3-dinitrobenzene (m-DNB) as a weak and small aromatic electron acceptor molecule. It should be noted that Nolte et al. have successfully observed the complexation of m-DNB using a glycoluril-based receptor bearing 2,7-dimethoxynaphthalene walls (Ka = (115 ± 10) M−1 ) [3 favorize donor–acceptor interactions and consequently the binding properties towards m-DNB. We have also checked the influence of the redox properties towards binding ability by studying the strong electrodeficient acceptor F4-TCNQ.In order to establish the influence of electronic and spatial properties of the clips towards binding ability of neutral electrodeficient guest molecules, we have chosen compounds 0) M−1 ) . In the 3 (10−3 M in o-C6H4Cl2) with addition of m-DNB (10−1 M in o-C6H4Cl2) aliquots. No additional change of the spectra was observed after the addition of one equivalent of m-DNB (−1.30 V vs Fc+/Fc) [o-C6H4Cl2 between clip 3 and m-DNB shows a maximum at 0.5, confirming the formation of the 1:1 complex (m-DNB@clip 3) (Ka = (7 ± 3) × 103 M−1 by exploiting the Job plot analysis according to literature [m-DNB using molecular clip 4, we could not observe any host–guest binding interaction. These results suggest that electronic and spatial properties of the cavity constitute fundamental parameters for binding the m-DNB guest. The binding of such a weak electron acceptor was successful for molecular clip 3 presenting the most suitable intramolecular distance between TTF sidewalls and the strongest π-donor ability.The host–guest affinity was detected by UV–visible spectroscopy upon titration of clip  Fc+/Fc)  which is@clip 3)  left. Thterature . Despite3 (5 × 10−4 M in CH2Cl2) was studied by a UV–visible titration with the electron acceptor F4-TCNQ (10−5 M in CH2Cl2). Addition of aliquots of molecular clip 3 onto a F4-TCNQ solution showed the presence of an isosbestic point at 395 nm with the concomittent formation and increase of bands at 760 and 860 nm which could be attributed to the progressive formation of the F4-TCNQ radical anion 2@clip 3 (Ka = (8 ± 5) × 108 M−1.A Job plot carried out in CH2@clip 3  middle w4 and quantitative measurements were performed using UV–visible titration considering the changes in the spectra of F4-TCNQ at 860 nm upon addition of sensor 4. The construction of the Job plot is in agreement with the 1:1 binding stoichiometry between clip 4 and F4-TCNQ with a maximum centered at a molar ratio of 0.5 (Ka = (1.3 ± 0.8) × 106 M−1 in CH2Cl2 confirms that this rigidified molecular clip 4 is an efficient receptor for F4-TCNQ guest electron acceptor.Similar studies were carried out using molecular clip o of 0.5  right. T3 and 4 towards the F4-TCNQ guest could be explained by their electrochemical properties. By comparing the first oxidation potential of clips 3 and 4 with the first reduction potential of F4-TCNQ 2@clip 3 complex should result from a redox interaction between the host and the guest. On the other hand, the oxidation potential of molecular clip 4 is increased due to the introduction of the naphthoquinone spacer. Consequently, the corresponding 1:1 stoichiometry should reasonably correspond to the binding of F4-TCNQ inside the cavity of clip 4  or strong (F4-TCNQ) electrodeficient guest. Consequently, the selectivity for a given target guest could be precisely tuned via the choice of the molecular clip according to its electrochemical and spatial considerations.We have presented original synthetic strategies leading to glycoluril-based molecular clips containing electroactive TTF sidewalls. In particular, the one-step preparation of molecular clip using the N-tetraalkylation of glycoluril constitutes a powerful versatile method allowing an easy access to new architectures for which electrochemical properties can be tuned by simple modification of peripheral substituents on the TTF moiety. Cyclic voltammetry and spectroelectrochemical measurements demonstrated that the mixed-valence state in these fused glycoluril-TTF molecular clips seems to originate from intermolecular TTF interactions, according to measurements at various concentrations and to cyclic voltammogram simulations. Spatial and electrochemical properties were shown to be fundamental parameters towards the binding interaction of a weak  as supporting electrolyte. All solutions were prepared and transferred into the spectroelectrochemical cell in a glove box containing dry, oxygen-free (<1 ppm) argon, at room temperature.Electrochemistry and time-resolved spectroelectrochemistry in solution were performed using the already described home self-made cell –45. ElecSpectrophotometric measurements were carried out in direct reflexing mode on the working electrode  with a homemade bench composed of different Princeton Instruments modules . The connection between the light source, the cell and the spectrophotometer is ensured through a “Y-shaped” optical fiber bundle: 18 fibers guide the light to the cell, and 19 fibers collect the reflected light from the cell to visible (320–1080 nm / maximum acquisition frequency 2 MHz) and IR (900–1700 nm / maximum acquisition frequency 8 MHz) CCD detectors. The sensitivity of the spectroscopic measurement  and 5000 electrons (low gain) between 900 nm and 1700 nm) allows performing a spectroelectrochemistry experiment under the usual conditions of electrochemistry.


Once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers, the nerve paths are something fixed, ended, and immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree” , and a number of articles from worldwide leaders in the field. Vicario-Abejón's group  has reviewed the action of IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. Mira's laboratory (Vilar and Mira) focused on the current understanding of neurotrophin modulation of adult neurogenesis, identifying both expected and unexpected functions for the neurotrophin protein family of ligands. De Marchis' group  reviewed the emerging aspects related to dopaminergic cells heterogeneity, molecular determinants of adult born dopaminergic neurons, their plasticity and function in the olfactory bulb. Kohl's laboratory  provides evidence that species and the specific strain largely matter when investigating effects of the generation of new neurons in neurogenic and non-neurogenic regions following dopamine agonists treatment. Avila's group  has focused their review on the morphological alterations of the dendritic tree of newborn neurons both in the physiological process and in neurodegeneration, while Tsuboi's laboratory  reviewed the molecular mechanisms that underlie the sensory input-dependent development of newborn interneurons and the formation of functional neural circuitry in the olfactory bulb.This Research Topic addresses half-century advances on all these topics from a multidisciplinary point-of-view. We suggest readers to begin with the editorial of a related Research Topic by Figueres and López-Mascaraque) addressed the distribution and neurochemical identity of adult olfactory bulb interneurons targeted at either embryonic or postnatal ages with a ubiquitously expressed transposable reporter vectors encoding eGFP. Raineteau's group  discusses the role of a strict spatial coding of segregated NSCs populations during oligodendrogenesis. Kuo's laboratory  emphasizes the relevance of how neural circuit-level input can be a distinct characteristic defining postnatal/adult NSCs from non-neurogenic astroglia. Ortega's group (Ortega and Costa) reviewed the state-of-the-art of live imaging as well as the alternative models that currently offer new answers to critical questions. Saghatelyan's laboratory  analyzes the pivotal role of astroglial cells in adult neurogenesis. Suarez's group  suggested a potential modulatory role for PPARalpha in the age-induced neurogenesis decline. Paredes' laboratory demonstrated that while mating behavior influences the process of olfactory bulb neurogenesis , sexual behavior induces long-lasting plastic changes in the olfactory bulb .López-Mascaraque's team  reviewed stroke-induced adult neurogenesis, from a cellular and molecular perspective, to its impact on brain repair and functional recovering. Parent's laboratory  reveals the Importance of adult neurogenesis in maintaining network stability and suggesting that this circuit is a potential target for anti-epileptogenic interventions. Encinas' team (Pineda and Encinas) discusses the mechanisms by which neuronal hyperexcitation influences hippocampal neurogenesis. Varea's group  shows a reduction in the number of proliferating cells in trisomic mice, although the final number of neurons integrated in the system is the same in Ts65Dn, a Down syndrome mice model. Lazarov's laboratory  discussed the association between impairments in adult hippocampal neurogenesis and cognitive deficits leading to Alzheimer's disease. Martínez-Marcos team  characterizes the neurogenic process in the olfactory bulb of APP/PS1 mice analyzing the neurogenic and neurodegenerative rates of new and preexisting interneuron populations. Finally, Trejo's team  hypothesizes on adult neurogenesis as a physical substrate for hormetic, biphasic dose-responses to exercise on cognition and mood.Malgrange's group (Fifty years after the birth of adult neurogenesis, the health of this field is very good, as demonstrated by this Research Topic, covering hot aspects of this area of Neuroscience. The data emerging from these 22 contributions addressed issues of fundamental importance for understanding how neural cells could be integrated into existing functional brain circuits. Furthermore, these contributions point to the fact that much more knowledge is still needed in basic features of adult neural cell genesis. The number of unexplored aspects of this field appears to be so measureless that we conclude that this is a healthy 50-years-old baby field. Hopefully, at the 75th anniversary, our field will be mature enough to cover the translational edge of this topic.AM, JT, and LL have written this editorial for the Research Topic they have edited.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The microblogging is prevailing since its easy and anonymous information sharing at Internet, which also brings the issue of dispersing negative topics, or even rumors. Many researchers have focused on how to find and trace emerging topics for analysis. When adopting topic detection and tracking techniques to find hot topics with streamed microblogging data, it will meet obstacles like streamed microblogging data clustering, topic hotness definition, and emerging hot topic discovery. This paper schemes a novel prerecognition model for hot topic discovery. In this model, the concepts of the topic life cycle, the hot velocity, and the hot acceleration are promoted to calculate the change of topic hotness, which aims to discover those emerging hot topics before they boost and break out. Our experiments show that this new model would help to discover potential hot topics efficiently and achieve considerable performance. Microblogging (post) is a mini blog which is typically smaller in both actual and aggregate file size comparing with a traditional blog. Microblogging allows users to exchange small elements of content such as short sentences, individual images, or video links. As a convenient communication means, especially with mobile phone, microblogging has been prevailing in the Internet. Sina Weibo (a Chinese Twitter) produces 25,000,000 messages each day, and Twitter gets 50,000,000 for each day.In our opinion, there are two main reasons that bring the bloom of microblogging. The first reason is the initiative of posting concerning messages of each person ranging from the simple such as “what I'm doing right now” to the thematic such as political theme. The second reason is that the mobile phone would help users to utilize the splitting time to concern the topics on the microblogging systems.With a large amount of reading and communication from users, it is quite understanding that hot topics would show up since most of people are concerned about those emergent incidents, such as “missing flight MH370.” Of course there are a lot of rumors since Internet is anonymous. It is a good way for local government and department to publish latest news about their work to dismiss rumors. However we argue that it is more important to discover those hot topics in advance. That means we need to construct a prerecognition model for hot topic discovery.Most of current work usually focuses on the postrecognition of hot topic discovery for analysis with history dataset. They are difficult to check the real-time status of topics, which is unfavorable to control those rumors. In this paper, we emphasize our work on the prerecognition mechanism and propose a novel hot topic discovery system which integrates previous hot topic discovery mechanisms with the concept of hot velocity and hot acceleration to recognize potential hot topics before they boost and break out.This paper aims to enhance our previous work on prerecognition of hot topic discovery . We firsThe rest of the paper is organized as follows. In Hot topic prerecognition is basically to aggregate those similar microbloggings, formalize topic clusters, and then rank topic clusters with the count of included posts, the hot velocity, and the hot acceleration.Much work has been done for topic discovery before microblogging's appearance. TDT (Topic Detection and Tracking) is one of the popular approaches. TDT aims to discover the topical structure in unsegmented streams of news reporting as it appears across multiple media and in different languages. Since hot topic discovery is focusing on real-time topic stream nowadays, we would like to introduce those online models. TID (Topic Initiator Detection)  introducCurrent work on emerging topic discovery with microblogging always applied several features of posts, such as textual information, graph connection, and the time factor to find those emerging topics.As for using textual information feature, Kasiviswanathan et al. identified emerging topics through detection and clustering of novel user-generated content in the form of blogs, microbloggings, forums, and multimedia sharing sites with dictionary learning approach . Goorha Considering the time factor, Zhu et al. proposed a method for discovering the dependency relationship between the topics of documents in adjacent time stamps based on the knowledge of content semantic similarity and social interactions of authors and repliers . Iwata eBesides the time factor, some researchers thought that the graph connection could be one of the important sources to detect emerging topics. Cataldi et al. made use of a term aging model to compute the burstiness of each term and provided a graph-based method to retrieve the minimal set of terms that can represent the corresponding topic . Zhou anSome other work combined more features for topic detection. Chen et al.  crawled Tu and Seng , He and Different from these models, we define the topic life cycle, the hot velocity, and the hot acceleration to recognize hot topics and use the microblogging dataset to examine our model. And our goal is to find those hot topics in advance. So in this paper, we combine the concept of topic model with the topic life cycle to define a prerecognition model for emerging topic detection.Before introducing the prerecognition model, we would like to give some related definitions for hot topic discovery.p is an original message crawled from a microblogging system published by a user u, which can be expressed as p = {p∣w1, w2,…, wn, n ≤ 20}.A post (microblogging) p as a sequence of keywords w from the view of NLP . Since a post is always limited with the word count (most of microblogging systems maximize the word count to 140), we assume that the maximum count of keywords w of a post is 20. Considering the particularity of the Chinese microblogging system, we generated the Chinese keywords from several basic corpus, including Sogou Pinyin input dict (http://pinyin.sogou.com/dict/), NLPIR microblogging corpus (http://www.nlpir.org/).The original message of a post always includes text, video link, audio link, images, retweet, and comment information. In this paper, we focus more on textual content in a post which inspires us to define the post 1, to2,…, tok, p1, p2,…, pj, k ≥ 0, j > 0}.A topic to is what posts are talking about and is composed of a set of posts. A topic may include a set of subtopics; thus it can be expressed as to = {to∣toi may derive sub-subtopics toim until a subtopic becomes a new topic representing totally different theme and cannot be derived at that time.Always a new topic is generated from a series of posts, whereas, with its evolution, a topic may derive subtopics which are discussing about the same theme but with partly distinct keywords. Of course a subtopic toAs we observed, when a topic is becoming a hot topic, the following conditions should be satisfied: (1) the topic amount is high enough, which means the number of posts included in the topic exceeds a predefined threshold; (2) the speed of the topic amount is high enough, which shows that the topic amount should increase quickly in a short time; (3) the acceleration of topic increment grows fast. tto describes how many posts p belong to current topic and its subtopics: ∑to = ∑ito∑pij + ∑pj.Topic amount ∑t: thv = ∑tto/t, t > 0, t%Δt = 0.Topic hot velocity thv is to express how fast a topic to increases, which is calculated with topic amount in a period time t is the minimized time period to process the original posts and get the topics.ΔTopic hot acceleration tha shows the speed of thv, which can be presented as the first derivative of topic hot velocity tha = thv′.As we have observed, when a topic is emerging, tha always gets high, which would be an important metric to determine whether a topic is hot or not.As shown in A topic life cycle defines topic status, which offers six status tlc = {embryo, boost, outbreak, stabilization, recession, extinction}.1. In this period, the topic amount is increasing slowly. When more people begin to concentrate on a specialized topic, the topic amount would increase in a very short time, in which stage we call boost presented as TLC2. In this period, the thv and tha are increasing continuously which makes this topic be a potential hot topic. When the topic amount and the thv are increasing continuously whereas the tha is increasing not so fast, in which stage we call outbreak presented as TLC3. In this period, the thv would achieve its maximum value. When the thv has a relatively fixed value, we call this period stabilization presented as TLC4. When a topic decreases quickly in a short time, we call this stage recession presented as TLC5. When a topic is almost not discussed, we call this period extinction presented as TLC6.In our opinion, a topic life cycle includes six periods: embryo, boost, outbreak, stabilization, recession, and extinction as shown in Also a topic life cycle has its periodicity according to the evolution of attention from the public, which means a topic may have several life cycles consequently.i∩tlcj}.A transformation point is the point between different periods of a topic life cycle expressed as tp = {tp∣tlcThe transformation point shows the status change for different periods of a topic life cycle. Thus we get five transformation points for a complete topic life cycle consequently.According to the above definitions, we can describe a hot topic as follows.ξ expressed as hotto = {hotto∣to ∈ boost, tp ∈ {boost∩outbreak}, ∑to ≥ ξ}.A hot topic would always be in the period of boost and the topic amount should exceed the threshold With the above definitions, we then offer the prerecognition model in detail at the next section.The first one is that our model aims to find those emerging topics before they are hot ones since we apply a prerecognition model, which can catch the instant changes of the topics on their topic amounts, topic velocity, and topic acceleration.We borrow the concepts of “velocity” and “acceleration” from physics, which can well illustrate the dynamics of the hot topics.ξ during the period of boost brings the success of the prerecognition model.We define the concept of topic life cycle, which can capture the periodic characteristics of hot topics. Moreover, calculating the ∑to ≥ As described above, different from other works on hot topic discovery, our contributions on hot topic discovery can be summarized as follows.ξ during the period of boost in a topic life cycle; thus three processes should be followed.Clustering the original posts to get topics and their amount: we also extend this process into five steps: filtering the original posts to omit the stop and useless words, matching the preprocessed words to get keywords, using LDA  and PAM Calculating the velocity and acceleration of the topic: we define several transformation points, threshold of thv and tha, to find the different periods of the topic life cycle.Selecting potential hot topics during the boost period through checking their ∑to, thv, and tha.The prerecognition model is to find those potential hot topics with ∑to ≥ http://weibo.com/), QQ (http://t.qq.com/), and Twitter (http://twitter.com/). We develop a crawler gathering posts' textual information with open APIs provided by these microblogging systems. It is important to note that a post may include hashtag which is a manually labeled hashtag expressed with #xx# (xx represents word term). In this paper, we extract #xx# as a topic directly since this token can express the semantics explicitly. For the other plain text, we need to extract keywords from the posts and then cluster the current keywords to generate topics. As we observed, a post can be viewed as a series of keywords that delivers the similar scenario of topic model. Topic model schemes each post as a mixture of topics, and each topic is a multinomial distribution over words in a vocabulary, which inspires us to introduce the topic model for post clustering. LDA is one of the increasingly popular tools for summarization and discovery with the capability of automatically extracting the topical structure of large document collections. LDA constructs a three-level hierarchical Bayesian model based on the idea of topics. Each document exhibits multiple topics with different proportions, and the topic proportions are document-specific and randomly drawn from a Dirichlet distribution. Each topic is also modeled as an infinite mixture over a set of words probabilities.The topic clustering step aims to classify streamed posts into different topics. We should first collect original posts from different microblogging systems, for example, Sina . θd is a document level variable which presents multinomial distribution over topic zn and ∑i=1kθ1 = 1. The zdn and wdn are word level variables which measure the multinomial probability of a word wn in document d with a topic zn.In the three-level Bayesian network of LDA, parameters LDA topic model helps to capture the correlations among words and improve the recall of topic discovery. However, it does not explicitly model correlations among topics; that is, topics are not just plain textual documents but present strong structural information among topics. The ignored correlations among topics limit LDA's ability to mine the underling context of topic . In thisθt1d)( from g1(α1), g2(α2),…, gs(αs). θtid). For each word w in the post, PAM samples a topic path zw of length Lw : 〈zw1, zw2,…, zwLw〉. zw1 is the root, and zw2,…, zwLw are topic nodes in T. zwi is a child of zw(i − 1) and it is sampled according to the multinomial distribution θzw(i−1)d)(. And then sample word w from θzwLwd), we , we 4), t as 1 hour. That means we will cluster posts and calculate topic parameters at each hour.We need to calculate three parameters for a topic: topic amount, topic hot velocity, and hot acceleration. Considering the time duration of topic clustering, we set the time interval ΔAccording to the definition of hot velocity and hot acceleration, we get the instants t and time t − Δt, that is, the post increment of a topic after a time interval Δt. Considertk and time tj.Similar to the calculating steps of the topic hot velocity, we get t. Considertj to tk.As described above, prerecognition model aims to find those topics before they become hot topics, so we should find which period a topic belongs to. In As shown in If a topic is in its embryo stage, we can get the following equation:1 between embryo and boost can be calculated as follows:The transformation point tp2 can be calculated as follows:The boost period and tp2 as α2.We record the 3 can be calculated as follows:The outbreak period and tp4 can be calculated as follows:The stabilization period and tp4 as α3.We record the 5 can be calculated as follows:The recession period and tp5 as α4.We record the The extinction period can be calculated as follows:2. We then rank these potential hot topics as our results.According to the calculating steps of each period of topic life cycle and corresponding transformation point, we can easily find those potential hot topics; that is, we can choose those potential hot topics at tpThe following codes give the recognition algorithm for hot topic discovery: see O((NT)τ(N + T)3), where N is the number of words, T is the number of latent topics, and τ is the number of topics appearing in a post. According to our observation, the number of topics included in a post would be less than 3, which inspires us to set τ = 3 for few computational costs. As a result, the computational complexity of LDA is O(((NT)×(N + T))3). The complexity of PAM is similar to the LDA except its depth of children (topic level); that is, the computational complexity of LDA is O(r × ((NT)×(N + T))3), where r is the depth of children. In this paper, we set the maximum value of r = 8 for reducing the computational costs. As for cluster generation, the complexity is O(T), where T is the total number of topics.For simplicity, we just omit the complexity of the clawers and only present the complexity of prerecognition model. The clustering steps include topic generation and cluster generation. As for topic generation, the total running time is O(n), where n is the number of posts.The topic parameter calculation complexity is linearly related with the the number of posts; that is, the complexity is We set a server cluster to evaluate the efficiency of our model. The cluster includes 10 PC servers, each server having 2 CPU, 32 GB memory, and 4 TB disk storage. We distribute 4 servers to collect the real dataset since the microblogging systems always limit the number of posts being crawled. The remaining servers are distributed for hot topic recognition. And all experiments are evaluated with 100 Mb bandwidth.We crawled approximately 2,000,000 original posts from Sina, QQ microblogging systems with their APIs. The dataset contained 675,439 valid posts after preprocessing to filter those meaningless ones (those posts with less retweet count than 500) from 2014/01/01 to 2014/04/30. Of course this dataset cannot include all posts because of the limit of API. However, we investigated that it is enough to validate our model since the crawled posts would cover almost all concerned topics. We choose our training dataset from 2014/01/01 to 2014/01/31 and other posts as test dataset. In the training dataset, there are 208,563 posts and 903,772 words which are identified by 80,000 terms.In our datasets, the topics and keywords are almost Chinese terms. Considering the particularity of Chinese microblogging system, we generate these Chinese terms from several basic corpora, including Sogou Pinyin input dict, NLPIR microblogging corpus. For those English keywords, we just use the standard corpus.http://www.cs.princeton.edu/~blei/lda-c/). When training LDA parameters, we figured out 500 latent topics manually from the training posts and get the parameters α = 0.05 and β = 0.1.We first cluster topics from the training dataset. We use C implementation of variational EM for LDA provided by Princeton University , amount of posts, amount of subtopics, the maximum level of subtopics, and average recall/precision after clustering process.As shown in τ = 60%.Also we observed that the recall/precision of most topics is not very high, which means some posts are ambiguous to be classified into one topic. In this paper, we aim to discover those potential hot topics quickly; we would like to improve recall of the topic, which inspires us to classify a post into a topic when its possibility is over a threshold 2. We made the simulated evaluation with the testing dataset and got the predict time and the corresponding topic hotness shown in http://www.google.com/trends/) and Baidu Index (http://index.baidu.com/) .We have summarized those hot topics with our clustering model; another problem is to find those potential hot topics in their transformation point tpWe should emphasize that topic amount and thv are far less than the query amount of Google and Baidu. However, we emphasized our focus on the predicting time for emerging hot topics. We observed that our result of finding a hot topic is always quicker than the query from search engine; this is because posts and topics are always published on the microblogging systems nowadays, then noticed by Internet users and traditional medias, and finally searched by interested people with search engines.ξ = 5,000, V1 = 800, and α1 = 800 to rank the potential hot topics comparing the scale of our dataset. Also these thresholds would be applied for real-time hot topics prediction.In our experiment, we set the thresholds The rapidity of prerecognition model for hot topic would be very useful for acquiring online public opinion, which helps to control rumors and guide the public opinion. Moreover, the advertisers can use this model to promote customized advertises to different users.As we observed, different topics have their special trend models of becoming hot topics in their topic life cycles. As shown in As shown in The second mode of topic hotness is shown in The third mode of topic hotness is shown in The fourth mode of topic hotness is shown in According to the analysis of four modes of hot topics, we can capture important keywords to monitor hot topics in advance and control public opinion correspondingly.We have noticed that a hot topic may be hotter and hotter in the third mode. However, there exist two situations for periodic hot topics as shown in A hot topic may present almost the same hot velocity at each life cycle for some special topics, such as “China Spring Festival.” These topics are concentrated at a fixed time and disappear when the events finish, and the concerned people and medias are always fixed. So the topic amount and topic hot velocity present the same speed at each life cycle correspondingly, which helps to capture these hot topics before the event shows up. Another scenario is that a hot topic may present higher hot velocity at each life cycle, such as “MH370 missing accident.” These topics would be focused on by more people with traditional medias involved in. When more and more people participate in the discussion, more and more posts are generated and certainly would result in higher topic velocity. In this scenario, any evidence or opinion may bring in more concentration.The regular pattern of periodic hot topics would help us to monitor those periodic hot topics when they are in their periodic time or when new breaking news show up.How to discover potential hot topics before they boost and break out on microblogging systems is a research focus, which also helps to guide rumor topics for government and deliver customized advertisement for e-business enterprise. In this paper, we scheme a novel prerecognition model for hot topic combining the generative model with the concept of the topic life cycle, the topic hot velocity, and the hot acceleration. We crawled test dataset from popular microblogging systems to verify our model. The experiments prompt that this prerecognition model can identify those emerging hot topics quickly.Still there are several issues that should be solved. The first one is that a comparison between the model proposed in this paper and other similar models should be given to improve the persuasiveness. And then a parallel clustering algorithm should be provided to process large scale of posts. Another problem is how to portray the evolution of topics which may change the theme and keyword set of the topic to a large extent. Also in this paper, we omitted the factor of involved users, which may be an important metric to calculate the hotness of the topic. In our future work, we would analyze these issues further and do the corresponding experiments for our model.


Soluble epoxide hydrolase (sEH) has C-terminal epoxide hydrolase and N-terminal lipid phosphatase activity. Its hydrolase activity is associated with endothelial nitric oxide synthase (eNOS) dysfunction. However, little is known about the role of sEH phosphatase in regulating eNOS activity. Simvastatin, a clinical lipid-lowering drug, also has a pleiotropic effect on eNOS activation. However, whether sEH phosphatase is involved in simvastatin-activated eNOS activity remains elusive. We investigated the role of sEH phosphatase activity in simvastatin-mediated activation of eNOS in endothelial cells (ECs). Simvastain increased the phosphatase activity of sEH, which was diminished by pharmacological inhibitors of sEH phosphatase. In addition, pharmacological inhibition of sEH phosphatase or overexpressing the inactive phosphatase domain of sEH enhanced simvastatin-induced NO bioavailability, tube formation and phosphorylation of eNOS, Akt, and AMP-activated protein kinase (AMPK). In contrast, overexpressing the phosphatase domain of sEH limited the simvastatin-increased NO biosynthesis and eNOS phosphorylation at Ser1179. Simvastatin evoked epidermal growth factor receptor–c-Src–increased Tyr phosphorylation of sEH and formation of an sEH–Akt–AMPK–eNOS complex, which was abolished by the c-Src kinase inhibitor PP1 or c-Src dominant-negative mutant K298M. These findings suggest that sEH phosphatase activity negatively regulates simvastatin-activated eNOS by impeding the Akt–AMPK–eNOS signaling cascade. Simvastatin (Zocor), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is a cholesterol-lowering drug that suppresses the biosynthesis of cholesterol and enhances the clearance of circulating low-density lipoprotein receptor (LDL) by upregulating the expression of hepatic LDR receptors123567Endothelium-derived NO is a cricial regulator of vascular homeostasis; dysregulation of eNOS is the key event in the initiation and progression of cardiovascular diseases such as atherosclerosis and hypertension911121314111214Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with C-terminal hydrolase and N-terminal phosphatase activity1617181920212223In contrast to knowledge of the hyrolase activity of sEH, that of its phosphatase activity is limited. Human sEH polymorphism studies demonstrated that Arg287Gln or Lys55Arg polymorphism of sEH, encoding a mutant sEH with reduced phosphatase activity, is associated with coronary heart diseases or type 2 diabetes252627293031In this study, we hypothesized that sEH phosphatase plays an important role in simvastatin-regulated eNOS activity. We investigated the change in sEH phosphatase activity with simvastatin treatment and then examined the effect of the phosphatase domain of sEH on simvastatin-induced eNOS phosphorylation and NO production as well as the Akt-AMP-activated protein kinase (AMPK) signaling pathway. We also delineated the mechanisms underlying sEH phosphatase-regulated eNOS activity in simvastatin-treated ECs. We found that sEH phosphatase is a crucial negative regulator of simvastatin-activated eNOS by activating epidermal growth factor receptor (EGFR)–c-Src signaling.We first validated the inhibitory effect of the sEH phosphatase inhibitors AFC or ebselen on sEH phosphatase activity in BAECs cells transfected with full-length sEH (WT) or the phosphatase domain of sEH (N-ter). These transfected BAECs were then treated with various concentrations of AFC  or ebselen  for 2 h. Our data showed that treatment with AFC or ebselen could dose-dependent inhibit the activity of sEH phosphatase activity , suggestSimvastatin can induce eNOS phosphorylation and NO production in ECs610To provide further evidence that sEH phosphatase is crucial in eNOS activation, we depleted the activity of sEH phosphatase by overexpressing a full-length sEH with catalytic-inactive phosphatase. Simvastatin-mediated eNOS phosphorylation at Ser1179 was further augmented with overexpression of the inactive phosphatase domain (PTmut), whereas overexpression of the inactive EH domain (EHmut) had no effect . In contThe Akt–AMPK signaling pathway plays a crucial role in simvastatin-activated eNOSThe physical interaction of eNOS with intracellular proteins such as Akt and AMPK is a key molecular mechanism in regulating eNOS activity14http://www.cbs.dtu.dk/services/NetPhos/)EGFR–c-Src signaling was predicted to be a pathway mediating sEH Tyr phosphorylation by use of the web tools NetPhos 2.0 and NetPhosK 1.0 , PP2A and PP2B are also involved in regulation of eNOS activitysEH phosphatase is thought to have isoprenoid mono- and pyrophosphate activity and prefer hydrolysis phosphates of lipophilic compounds in cells3931in vivo is difficult. Indeed, several lines of evidence suggest that genetic ablation of sEH exacerbates the progression of many diseases, albeit with an unclear mechanism43The biological role of sEH hydrolase activity and its substrate EETs in the functioning of the cardiovascular system and the development of cardiovascular diseases is well established1718192441In addition to the kinase- and phosphatase-dependent regulation of eNOS activity, physical interaction of eNOS with intracellular proteins is a crucial mechanism in regulating eNOS activation with stimuli1436ECs play a crucial role in regulating vascular homeostasis, including blood cells and nutritional trafficking to tissues, coagulation and vascular tone956718In summary, we provide new evidence that simvastatin activates EGFR–c-Src signaling, which increases Tyr phosphorylation of sEH and sEH–Akt–AMPK–eNOS interaction. These events may work in concert to modulate simvastatin-induced eNOS activation and NO production in ECs. The molecular mechanisms we reveal may provide new information for better understanding the regulation of eNOS activation and for suggesting novel pharmacological targets for treating eNOS-related cardiovascular diseases.Rabbit antibody (Ab) for phosphor-eNOS at Ser1177, phosphor-Akt at Ser473, phosphor-AMPK at Thr172, phospho-epidermal growth factor receptor (EGFR) at Tyr845, phosphor-c-Src at Tyr416 and mouse Ab for phosphor-Ser and phosphor-Thr were from Cell Signaling Technology . Rabbit Abs for eNOS, sEH, Akt, and AMPK; mouse Ab for EGFR; and protein A/G PLUS-Agarose were from Santa Cruz Biotechnology . Mouse Ab for phosphor-Tyr was from BD Biosciences  and for α-tubulin, simvastatin, PP1, 4-nitrophenyl phosphate, ebselen and Griess reagent were from Sigma-Aldrich . ECL Cell Attachment Matrix was from Millipore . N-acetyl-S-farnesyl-L-cysteine (AFC) was from Enzo Life Sciences . 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid (AUDA) and AG1478 were from Cayman .2 incubator at 37 °C.Bovine aortic endothelial cells (BAECs) were purchased from Cell Applications  and cultured in Dulbecco’s modified Eagle’s medium with 10% fetal bovine serum, 100 unit/ml penicillin and 100 mg/ml streptomycin  in a humidified 95% air and 5% COTreated BAECs were collected in phosphate buffered saline (PBS), which was sonicated, and supernatant was collected by brief centrifugation. The cell lysate supernatant was added to 4-nitrophenyl phosphate to 2 mM and incubated in 37 °C for 1 h. The yellow color product was detected by OD 405 nm to determine phosphatase activity.Griess reagent was used to evaluate accumulated nitrite, the stable breakdown product of NO, in culture media. After incubation of an equal volume of Griess reagent with medium from treated cells at room temperature for 15 min, the solution was evaluated by SP-8001 UV/VIS spectrophotometry (Taipei) to detect azo dye production at OD 540 nm. Sodium nitrite was used as a standard.sEH N-terminal phosphatase domain (N-ter) and C-terminal hydrolase domain (C-ter) were amplified from mouse cDNA by PCR with the primers 5′-TTA CGC GTG CGC TGC GTG TAG CCG-3′ and 5′-GGT CTA GAC TAC CCT GTG ACC TTC TCC A-3′ for N-ter and 5′-TTA CGC GTG TCA GCC ATG GAT ATG TGA C-3′ and 5′-GGT CTA GAC TAA ATC TTG GAG GTC ACT G-3′ for the C-ter. The protocol was 2 min at 94 °C, then 15 sec at 94 °C, 30 sec at 58 °C and 2 min at 72 °C for 35 cycles. PCR products were digested with MluI and XbaI for cloning into pCMV5N-Flag vector. The sEH full-length cDNA and sEH with mutant hydrolase or phosphatase domain {WT, Ehmut, or Ptmut, respectively; kindly provided by Dr. S. Imaoka MluI and XbaI-digested PCR products were cloned into the pCMV5 N-Flag vector. The c-Src mutant plasmid, K298M, was kindly provided by Dr. KL Guan .Coding regions for the g for 5 min and supernatant was collected. Aliquots (50 μg) of cell lysates were separated by 8% SDS-PAGE and transblotted onto Immobilon-P membrane . After being blocked with 5% skim milk in Tween/PBS, blots were incubated with primary Abs, then with horseradish peroxidase-conjugated secondary Abs. The protein bands were detected by use of an enhanced chemiluminescence kit and quantified by use of ImageQuant 5.2 .BAECs were lyzed with SDS lysis buffer , 10 μg/ml aprotinin, 1 μg/ml leupeptin], then centrifuged at 12,000 g for 10 min. Aliquots (1000 mg) were incubated with anti-sEH Ab overnight at 4 °C, then 20 μL Protein A/G PLUS-Agarose was added for 2 h in 4 °C. Immune complexes were collected by centrifugation and washed 3 times with ice-cold PBS. The supernatant was discarded and the pellet was resuspended in SDS lysis buffer, then boiled with 1X SDS loading dye for 5 min. Protein was separated by SDS-PAGE and transferred to PVDF membranes and incubated with various Abs.BAECs were lyzed with IP lysis buffer . After brief sonication on ice, cellular debris was removed by centrifugation at 10,000 sEH was obtained from mouse cDNA and sub-cloned into the pM vector  with MluI and XbaI cutting sites. eNOS, Akt and AMPK cDNA were obtained from human cDNA and sub-cloned into the pVP16 vector  with HindIII, EcoRI and EcoRI cutting sites, respectively, and confirmed by sequencing. Secreted human alkaline phosphatase (pG5SEAP) and plasmids were co-transfected into BAECs by use of Lipofectamin 2000 for 48 h, then treated with or without simvastatin  for an additional 24 h. Culture media was collected and underwent chemiluminescence assays by use of GreatEscAPe SEAP chemiluminescence detection kits .Full-length Tube formation measurement was performed as describedP < 0.05 was considered statistically significant.Data are shown as mean ± SEM from 5 independent experiments. Mann-Whitney test was used to compare two independent groups and Kruskal-Wallis analysis was used with Bonferroni post-hoc correction to account for multiple testing. Statistical analysis involved use of SPSS v8.0 . How to cite this article: Hou, H.-H. et al. Role of phosphatase activity of soluble epoxide hydrolase in regulating simvastatin-activated endothelial nitric oxide synthase. Sci. Rep.5, 13524; doi: 10.1038/srep13524 (2015).


This study compared the effectiveness of auditory and visual redirections in facilitating topic coherence for persons with Dementia of Alzheimer's Type (DAT). Five persons with moderate stage DAT engaged in conversation with the first author. Three topics related to activities of daily living, recreational activities, food, and grooming, were broached. Each topic was presented three times to each participant: once as a baseline condition, once with auditory redirection to topic, and once with visual redirection to topic. Transcripts of the interactions were scored for overall coherence. Condition was a significant factor in that the DAT participants exhibited better topic maintenance under visual and auditory conditions as opposed to baseline. In general, the performance of the participants was not affected by the topic, except for significantly higher overall coherence ratings for the visually redirected interactions dealing with the topic of food. Healthcare providers rank individuals with dementia as the third most common disorder served on their caseloads . It is wpoor topic maintenance and reduced inclusion of core elements required by the topic –9,reference errors, sentence fragments, and difficulty formulating and remembering the content of sentences , 5, 10,circumlocution, perseveration, and revisions , 11.While healthy elderly adults have been found to be able to confine themselves to one topic when instructed , personsAnother discourse variable which has been studied in DAT includes topic relevance. Individuals with DAT have been found to produce a high proportion of irrelevant information and slightly more redundant information than healthy elderly controls . Even miOther literature has attempted to measure the coherence of DAT discourse. Persons with DAT were found to be significantly impaired with respect to global coherence  relative to normal controls , 16. In Paraphrasing relevant ideas .Asking yes/no questions to structure the repair .Restating the topic, repeating ideas, or providing missing information .Removing embedded clauses, using one idea per utterance, and using gestures to supplement caregiver verbalizations , 26.Given the deficient coherence in DAT discourse, need for discourse repair is apparent. Various authors , 21, 22 It appears as if the effectiveness of caregiver repair strategies is somewhat dependent upon severity of DAT, with more success occurring during earlier stages of the disease. Various authors , 27 haveGentry and Fisher  investigVarious visual and auditory cues have been used by investigators to improve communication. For instance, Bourgeois  attempteFried-Oken et al.  comparedA revision to the above study included a training component whereby participants with DAT received spaced retrieval training in order to familiarize them with the picture layout of the low-tech AAC visual support prior to data collection. The authors found that the addition of the training component plus the visual-only AAC support increased use of target words in conversation .Previous research has been comprehensive in describing the characteristics of discourse in persons with DAT. A few studies have focused on topic relevance and repair with most studies indicating the burden of repair falls to the nonimpaired conversational partner. Mixed results have been found in relation to what types of caregiver cues  best support communication, and, to our knowledge, no studies have looked directly at the effects of caregiver cues on topic maintenance/coherence regarding topics related to activities of daily living. Given the focus on indirect techniques to improve communication for persons with DAT found in the literature, a system of caregiver cueing should be explored to determine its effects on improving in-the-moment conversational interactions between persons with DAT and their caregivers.Can manipulation of a conversational partner's role in interactions with persons with DAT effect a positive change in DAT participants' topic maintenance skills?Will a visual redirection to topic improve the topic maintenance skills of persons with DAT?Will an auditory redirection to topic improve the topic maintenance skills of persons with DAT?Will there be a difference in the effectiveness of visual versus auditory redirections?Therefore, it was proposed that studying ways to manipulate how individuals converse with persons with DAT might yield changes in the conversational output of persons with DAT. In contrast to earlier studies, the present study put virtually no restraints on how the persons with DAT chose to interact. Instead, it looked to improve topic maintenance in interactions with persons with DAT by changing the way a conversational partner interacted with them. Specifically, the following research questions were posed:Prior to administering the research task, five healthy elderly (HE) adults were recruited from an assisted living facility to ensure that age- and education-matched peers would be able to exhibit the expected topic control required of the task . They weFive adults with language disorder secondary to DAT participated in this study. They were selected from a memory-loss unit at the same assisted living facility as the adults who piloted the research task. A neurologist had provided a diagnosis of probable DAT for all participants. Demographic information regarding participant status is summarized in Each participant was rated using the Global Deterioration Scale (GDS) . The GDSPersons rated at levels 5 and 6 on the GDS were targeted for the study. Azuma and Bayles [M = 18.12) and moderate DAT  . All DATParticipants for either group were excluded if they had any prior history of psychological, neurological, language, or speech disorder. They were also excluded if any history of drug/alcohol abuse was reported. All participants had vision and hearing, corrected if needed, adequate to perform the task. This was confirmed by participant self-report and by staff from the assisted living community.Consent to participate was obtained from each participant's caregiver. Then, a detailed case history was obtained for each. The DAT participants were asked to give verbal consent at the beginning of each session. Also, the day-to-day assent of the participant was considered withdrawn if the primary investigator observed continued signs of agitation on the part of the participant. Regarding assent, one participant was too agitated to begin the procedures on one day. The investigator came back another day at which time the participant was able to tolerate the procedures. The approximately 20 minutes needed for the daily conversations was short enough that no participants became agitated once they entered the room where conversations took place. Testing took place in a quiet environment familiar to the participant. The participant and the primary investigator sat in close proximity, enabling them to see each other and the stimulus materials used in the visual condition. All procedures were audio- and video-recorded across three days, as described below.Baseline data was obtained from three five-minute interactions with each participant. One baseline conversation took place for each of the three days. Baseline conversations were paired with one auditory-redirected conversation and one visually redirected conversation for each day. In this manner, all three topics and all three conditions were presented only once each day to reduce potential perseveration . During each interaction, three different topics that represent commonly occurring daily living activities were presented . Enabling persons with DAT to better communicate regarding these topics would be highly ecologically valid. Also, the authors felt that improving communication in these situations would result in better quality of life for the participants.The primary investigator opened each conversation by using an open-ended question. For the activities topic, the participant was asked, “What would you like to do today?” For the food condition, participants were asked, “What would you like to eat today?” And for the grooming condition, participants were asked, “What do you do to get ready in the morning?” These prompts were chosen due to there being normally occurring efforts to initiate communication around daily living events. The primary investigator's role in these interactions was limited to providing minimal turns. Minimal turns were defined as any short utterance that provided no additional content to the conversation but simply turned the conversation back to the participant. The primary investigator only deviated from this procedure if the conversation was at a standstill. For the baseline condition, a standstill was defined as the participant not taking a conversational turn with corresponding silence for 10 seconds. At a standstill, the primary investigator asked, “Is there anything else you'd like to tell me?” The topic was not restated.In the auditory condition, the same three topics were introduced in the same format as the baseline condition. Each interaction was set to last for five minutes. Progress in the interaction was evaluated every 30 seconds as timed with a stopwatch. If the participant was successful at maintaining the topic, the primary investigator only took minimal turns. If the participant was off topic, an auditory cue  was interjected by the primary investigator. Once an auditory cue was given, the primary investigator returned to taking minimal turns. Thirty seconds later, progress was again evaluated with the primary investigator making the same forced-choice decision, using only minimal turns if the interaction remained on topic or providing the same auditory cue if the discourse had deviated from the topic.Photographs corresponding to the three topic areas  were placed in front of the primary investigator and the participant for the visual condition. Photographs chosen for the study were those that could be correctly named by the healthy elderly adults in one try. The pool of photographs relating to each topic was then narrowed down by asking the healthy elderly adults to choose the six photographs per topic that they felt would best help them answer the questions to be presented . (See the Appendix for a list of photographs used for each topic.)One card containing six photographs organized in two rows of three and pertaining to a specific topic was used for each five-minute interaction. The primary investigator directed the participant's attention to the photos and opened each topic in the same manner as for the other two conditions. At the end of every 30 seconds, progress was evaluated. If the participant was successfully maintaining the topic, the primary investigator took minimal turns. If the participant was off topic, the primary investigator called the participant's attention to a specific photograph without using the word for the target concept depicted in the picture by stating, “What about this?” For the succeeding thirty seconds, the primary investigator took minimal turns. Progress was evaluated in this manner every thirty seconds. Conversations took place in the midmorning or midafternoon as per facility wishes. The primary investigator aimed for times that would be approximately two hours after the most recent meal as well as two hours prior to the next meal to minimize potential effects of hunger on the conversations about food.The order in which each subject participated in visual versus auditory versus baseline conditions was pseudorandomized with the following constraints: persons with DAT were only allowed to participate in three interactions daily in an attempt to reduce possible perseveration. Therefore, each of the three topics was represented daily. Therefore, for both conditions and topic, all three conditions and all three topics had to be presented daily . With three conditions  and three topics , nine potential condition × topic pairs existed . The order in which these possible pairs were presented was then randomly assigned. The primary investigator administered all tasks.Picture stimuli for the visual condition were rotated between interactions with participants to negate any possible ordering effects of picture presentation. Eye contact and tactile stimulation were maintained in all conditions, as tolerated and appropriate, to increase the likelihood of the participant's continued attention to the task. Tactile stimulation consisted of squeezing each participant's hand when entering the testing environment in an attempt to orient the participant's attention to the primary investigator. This was accompanied by the statement “Thank you for talking with me today.”All conditions were audio- and video-recorded. A simple nonverbal distractor task  was presented between topics to decrease the likelihood of perseveration from interaction to interaction. A total of 3 days were needed to complete the 9 experimental interactions (3 topics × 3 conditions ÷ 3 conversations per day). At the end of each five-minute conversation, the primary investigator thanked the participant for sharing his/her ideas about the topics to signal the end of the conversation. If conversations went slightly beyond five minutes, only the first five minutes were transcribed to be analyzed.Videotapes of the interactions were reviewed, and typed transcripts of the first five minutes of each interaction were completed by both the first author and a graduate student in a speech-language pathology program who was trained by the first author. In a sample of 25% of transcripts completed by both transcribers, there was greater than 95% agreement in all aspects of transcription.Five minutes was chosen as the target for the conversations so that they should be sufficiently long to ensure that the cuing system would be used. The authors felt that a shorter interaction would not provide enough 30-second intervals at which cues might be useful. The five-minute timing of interactions will be further deliberated in the Discussion. Gestures that were noticeable on video were included in the transcripts in brackets. Gestures, by themselves, were not scored. However, gestures that added context to a participant's spoken utterance were scored with that utterance.The primary investigator first scored all transcripts while viewing the videotape. A second rater, thoroughly trained in the procedures, viewed the tapes of approximately 25% of the interactions and scored them for reliability purposes. Transcripts to be scored by the second rater were randomly selected.A score of 1 indicated that the participant's utterance did not relate to the initially stated topic at all .A score of 2 was assigned if the utterance contained a vague reference to topic, perhaps with no specific referent .A score of 3 corresponded to an on-topic statement not related to the present day .A score of 4 was assigned if an on-topic statement diverged slightly from its relevance to the present day .A score of 5 was awarded if the participant's utterance was logically related to all elements of the topic . Therefore, when the original statement of topic was “What would you like to eat today?” the participant had to address the time factor appropriately (today) as well as the general subject matter (favorite foods) in order to receive a score of 5. The authors believed that the factor of time was relevant to determining the participants' current likes/dislikes to participate in conversations about ADLs efficiently.Any utterance on which the primary investigator's and second rater's assigned scores differed by more than 1 point was rectified by a consensus of both scorers. In cases where scores differed by only one point, the primary investigator's score was used. Interjudge reliability scores were computed by the following formula:Each utterance was coded on a 1–5 global coherence scale adapted from Glosser and Deser . Scores An overall coherence score was calculated from each transcript. Overall coherence was defined as the ratio of the total number of points awarded to the total number of possible points for that interaction. This score represented the topic maintenance abilities of each participant for each entire interaction regardless of the presence  or absence (baseline) of primary investigator-directed cues to topic.d = 5.29). To replicate the condition × topic interaction whereby coherence for the visual redirection/food topic combination was significantly higher than other visually redirected topics and the auditory redirection/activities topic combination yielded better coherence than other topics under auditory redirection, four participants would be needed (effect size d = 1.75). Therefore, the number of participants (five) was sufficient to support the significance of the findings.Overall coherence data was analyzed by two-way ANOVA (condition × topic). Subsequent post hoc testing was completed as needed. Subsequent to the study, a power analysis  was perfPiloting with healthy elderly (HE) adults revealed that, using the stated procedures, all healthy elderly pilot participants achieved near-ceiling-level topic coherence abilities for the experimental task as expected. Topic coherence for these HE participants averaged 0.82 (or roughly 4.1 points out of 5 for each utterance) for all topics. This is consistent with data reported by Glosser and Deser  who repoMean overall coherence scores across topics and conditions for DAT participants are found in F = 25.127, p < 0.05), with no significant difference for topic  = 0.253, p > 0.05). There was one significant two-way interaction. Condition × topic significantly interacted  = 3.315, p < 0.05).Results of two-way ANOVA (condition × topic) found significant differences for condition  = 0.626, p > 0.05). The auditory condition did produce a statistically significant difference in DAT performance  = 5.014, p < 0.05). Newman-Keuls post hoc analysis revealed that auditory redirections resulted in overall coherence scores to be highest for the topic of activities . Scores for this topic were significantly higher (p < 0.05) than the food and grooming topics  which did not differ from each other. For the visual condition, a significant difference was also found  = 6.174, p < 0.05). Post hoc testing showed that, under visual redirection, DAT participants performed significantly better (p < 0.05) for the food topic  than they did for either activities  or grooming . The latter two topics were not statistically different.To further explore the performance of the DAT participants, six one-way ANOVAs were completed: one for each condition and one for each topic. Overall coherence scores did not differ significantly in the baseline condition across the three topics  = 25.923, p < 0.01), with the auditory and visual conditions yielding significantly higher overall coherence scores (p < 0.05) than the baseline procedure. The topic of food yielded a statistically significant difference  = 35.712, p < 0.01) between all three conditions with overall coherence scores for the visual condition being greater than for the auditory condition (p < 0.05) which was greater than the baseline condition (p < 0.05). A significant difference also was found for the topic of grooming  = 6.778, p < 0.05). Baseline scores were found to be significantly lower (p < 0.05) than the scores obtained during the auditory and visual conditions, which did not differ.For the topic of activities, significance was attained  test was completed . As therThe purpose of this study was to determine the effectiveness of auditory and visual redirection to topic on the connected discourse of persons with Dementia of Alzheimer's Type (DAT). Specifically, the redirections were intended to yield better in-the-moment topic maintenance for topics of daily significance. This research contributes to the literature by exploring the effects of caregiver cues on topic maintenance/coherence regarding topics related to activities of daily living. In addition, the research found that both the auditory and the visual redirections given by the caregiver were successful in improving the DAT participants' topic coherence. The measure of topic maintenance used for this study was taken from Glosser and Deser . In thatThe first research question addressed how changes in a conversational partner's role would impact the topic coherence of persons with DAT. Indeed, results showed that DAT participants can be successfully redirected to a topic, resulting in better overall coherence (the relatedness of every utterance in an interaction to the topic) when either type of redirection was present. These findings are consistent with numerous authors who have reported that communication repair, initiated by the caregiver of a person with DAT, is successful , 28.DAT participants in this study achieved a mean overall coherence score during baseline conditions of 0.32 (or roughly 1.6 points per utterance). This confirmed findings indicating that high proportions of irrelevant information were present in the discourse of persons with DAT . In contThe secondary goal of the study was to determine whether visual and/or auditory redirections to topic improved topic coherence for persons with DAT. Further, the researchers queried whether there would be a difference in effectiveness between the two modalities of cueing. Results showed that both auditory and visual redirections were equally effective in redirecting participants to a particular topic. Specific to auditory redirections, the present study found that auditory redirections increased topic coherence significantly above baseline levels. This finding is consistent with research which found that the most effective form of repair initiated by the conversational partners was in an auditory format  , 24. TheThe current results regarding visual redirections also showed improved topic coherence as compared to baseline conversations. These results support the findings of Fried-Oken et al.  who deteOf interest in this study, two condition × topic pairs were found to significantly improve DAT participants' topic maintenance skills above and beyond the general improvement noted. First, the visually redirected topic of food yielded significantly higher scores for persons with DAT than any other topic under the visual condition. It is possible that persons viewing the pictures had a somewhat visceral reaction, creating more robust discourse and enthusiasm for maintaining topic. DAT performance approached the performance of the pilot HE group for this specific communicative interaction. Also, the auditorily redirected topic of recreational activities brought about significantly higher performance for DAT participants than any other topic under the auditory condition. Persons with DAT may have viewed the primary investigator as a potential partner for engaging in the day's activities, thus yielding more relevant comments. The performance of the pilot HE participants in this study was unremarkable as their performance approached a ceiling effect.Unlike previous research, the present study attempted to make the utterances of persons with DAT more relevant during discussions about topics related to activities of daily living. Participants were provided with auditory and visual redirections to topics. Redirections were used as intervention in this study based on the findings of Watson et al.  who repoThe present study showed that structured partner-initiated repair, in the form of auditory or visual redirections, was beneficial to the topic maintenance skills of persons with DAT see . These fFurther research in this area should be explored. With a larger sample size, some effects that were not present in this study might be found. Adding participants in more mild and severe stages of DAT might also yield some cross-sectional data about the effectiveness of redirection on topic coherence in multiple stages of the disease. Similarly, getting information on coherence abilities from DAT participants who have different levels of education might be of interest. Although one participant in this study had a relatively low level of education, her scores on the ABCD matched closely with the other participants. As a result, we felt that it was appropriate to include her in our analysis given her similar cognitive-linguistic skills. For all DAT participants, a measure of day-to-day variation in performance should be investigated. Finally, a measure of caregiver satisfaction with the redirection system would be of use.Methods for this type of research may need to be revised. In retrospect, a five-minute time limit on interactions was thought to be excessive. Some of the healthy elderly pilot participants reported finding it very difficult to sustain such limited topics for five minutes. Many of the healthy elderly participants would have required no redirection if the interaction was shorter. In the future, cues should be revised such that the visual redirection is purely visual. In the current study, the visual redirection used also had an auditory component. One cannot be certain that the effect of the “visual” condition was due to the presence of the pictures alone. It would be interesting to see the effects of a pure auditory cue, a pure visual cue, and an auditory-visual cue. Also, there were six choices available as visual cues in the visual condition . Conversely, there was only one standard cue  for the auditory condition. Although the auditory cue was differentially effective at redirecting conversations about activities, it would be important to know if a cueing system with six choices, such as the visual cueing system, would yield different results. In addition, limited statistics were completed to measure effect sizes of the available data. However, visual inspection of the data and use of Nonoverlap of All Pairs (NAP) analysis indicate strong effectiveness of visual and auditory redirections on topic coherence when compared to baseline conversations.Cues were chosen based on items that healthy elderly individuals felt were most representative in answering the topics broached so that a standardized set of cues could be used. Future research might look at how person-centered choices of cues for each individual with DAT might change the results. In addition, the cues in the present study were designed more as direct repair strategies . Since GThis study added to the literature regarding caregiver role in repairing discourse with persons who have DAT. A systematic set of cues (redirections) was successful in eliciting discourse that remained at a high level of topic coherence. Both auditory and visual redirections yielded relevant information from persons with DAT in relation to topics necessary for daily living. This information could be used to further explore the effectiveness of simple, indirect redirections to topics of daily significance with larger and more diverse groups of persons with DAT. In addition, long-term use of the cueing system could be explored to determine whether any gains are made once the interactions are made more procedural and therefore routine.


Development of resistance against first line drug therapy including cisplatin and paclitaxel in high-grade serous ovarian cancer (HGSOC) presents a major challenge. Identifying drug candidates breaking resistance, ideally combined with predictive biomarkers allowing precision use are needed for prolonging progression free survival of ovarian cancer patients.Modeling of molecular processes driving drug resistance in tumor tissue further combined with mechanism of action of drugs provides a strategy for identification of candidate drugs and associated predictive biomarkers.Consolidation of transcriptomics profiles and biomedical literature mining results provides 1242 proteins linked with ovarian cancer drug resistance. Integrating this set on a protein interaction network followed by graph segmentation results in a molecular process model representation of drug resistant HGSOC embedding 409 proteins in 24 molecular processes. Utilizing independent transcriptomics profiles with follow-up data on progression free survival allows deriving molecular biomarker-based classifiers for predicting recurrence under first line therapy. Biomarkers of specific relevance are identified in a molecular process encapsulating TGF-beta, mTOR, Jak-STAT and Neurotrophin signaling. Mechanism of action molecular model representations of cisplatin and paclitaxel embed the very same signaling components, and specifically proteins afflicted with the activation status of the mTOR pathway become evident, including VEGFA. Analyzing mechanism of action interference of the mTOR inhibitor sirolimus shows specific impact on the drug resistance signature imposed by cisplatin and paclitaxel, further holding evidence for a synthetic lethal interaction to paclitaxel mechanism of action involving cyclin D1.Stratifying drug resistant high grade serous ovarian cancer via VEGFA, and specifically treating with mTOR inhibitors in case of activation of the pathway may allow adding precision for overcoming resistance to first line therapy. Development of drug resistance represents a major challenge in cancer therapy. In case of high-grade serous ovarian cancer (HGSOC), accounting for 60–80 % of epithelial ovarian carcinoma, initial sensitivity to standard platinum-based therapy is around 80 %. However, relapse rates in more advanced stages reach up to 70 %, with a first appearance varying from a few months to more than 5 years , 2. In cSeveral molecular mechanisms leading to drug resistance, being generic across drug classes or specific for a selected drug are described . A promiWith the advent of omics profiling explorative analysis of large sets of molecular features associated with disease development and progression became feasible. Generic analysis of omics datasets focuses on identification of individual molecular features exhibiting significant differences in abundance e.g. in case-control studies . More reIn this work we present a HGSOC molecular process model resting on an interaction network of molecular features associated with platinum-based drug resistance as identified in transcriptomics studies, further complemented with protein coding genes mined from scientific publications. We use this model representation to identify core molecular processes afflicted with drug resistance specifically triggered by a combination therapy of platinum-based drugs and taxanes. With such drug resistance molecular processes as basis, screening for drug targets, drug mechanism of action interference and predictive biomarker candidates becomes feasible.A data analysis overview is depicted in Fig. (“Ovarian Neoplasms/genetics” [majr]) OR (“Ovarian Neoplasms/pathology” [majr]) OR (“Ovarian Neoplasms/physiopathology” [majr]) OR (“Ovarian Neoplasms/enzymology” [majr]) OR (“Ovarian Neoplasms/chemistry” [majr]) OR (“Ovarian Neoplasms/metabolism” [majr]) AND  AND “humans” [mh]. 5663 publications were identified and used to retrieve gene annotation provided by NCBI gene2pubmed, resulting in 777 unique human protein coding genes (LIT-HGSOC dataset).Protein coding genes associated with drug resistant high-grade serous ovarian cancer were retrieved by querying the scientific literature, further extended by including results from transcriptomics studies. For mining scientific literature the following NCBI PubMed query was executed: This set of literature-based molecular features was complemented by protein coding genes derived from two transcriptomics studies in focus of disease relapse under platinum-based drug therapy. A first set of 432 molecular features was extracted from a study performed by Helleman et al., presenting a meta-analysis of nine individual transcriptomics studies, all focusing on HGSOC relapse in the context of platinum-based drug therapy (TX-HELLEMAN dataset) . A seconFinally, the three molecular feature sets LIT-HGSOC, TX-HELLEMAN, and TX-VERHAAK were combined into a set of 1,242 unique protein coding genes.Consolidated molecular features associated with drug resistant HGSOC were mapped on a hybrid interaction network including protein-protein interaction data from IntAct, BioGrid, and Reactome together with computationally inferred relations . 1202 ouCisplatin[mh] (LIT-CISPLATIN dataset) and Paclitaxel[mh] (LIT-PACLITAXEL dataset), respectively. An additional drug MoA molecular model was derived for the mTOR inhibitor sirolimus applying the PubMed query Sirolimus[mh] (LIT-SIROLIMUS dataset).Cisplatin and paclitaxel are selected as representative compounds for platinum-based and taxane-based therapies, respectively. Drug mechanism of action molecular models were generated for these two compounds following the procedure applied for deriving the HGSOCr molecular model. Molecular feature sets characterizing drug effect were retrieved via gene2pubmed feature assignments to publications identified with the PubMed query Interference of a drug MoA molecular model and the HGSOCr molecular model is determined as number of molecular features being part of the respective drug MoA molecular model as well as being part of the HGSOCr molecular model.p-values were adjusted for multiple testing using the Benjamini-Hochberg correction method.Molecular pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool  was condThe transcriptomics dataset from Ferriss et al.  was usedSynthetic lethal interactions of protein coding genes embedded in drug mechanism of action molecular models were retrieved from BioGRID. Interactions with experimental evidence tags “Synthetic Lethality” or “Negative Genetic” for the organisms Homo sapiens, Saccharomyces cerevisiae, Mus musculus, Gallus gallus, Caenorhabditis elegans, and Drosophila melanogaster were included. Orthology mapping from non-human model organisms to the corresponding human genes were based on orthology information as provided by Ensembl.Two transcriptomics datasets, TX-TOTHILL and TX-YOSHIHARA, not included in deriving the HGSOCr molecular model were used in order to evaluate the prognostic potential (time to relapse) of molecular features embedded in the HGSOCr molecular model. Raw transcriptomics data files were retrieved from GEO for the studies of Tothill et al.   and YoshFor retrieving expression profiles of resistant and sensitive patient cohorts the Affymetrix microarray data from TX-TOTHILL were processed using the affy R package applying RMA normalization.For the Agilent-based data set TX-YOSHIHARA the R limma package was used for data preparation with the normexp background correction method and quantile normalization, averaging duplicate features after normalization.adj) value for a logistic model only using features from the transcript feature panel as explanatory variables was calculated for each of the two datasets with AUCadj = AUCobs – (AUCboot – AUCtest), where AUCobs is the training AUC achieved on the entire dataset, AUCboot is the training AUC achieved on the bootstrapped data set and AUCtest is the AUC of a predictor trained on the bootstrapped data set tested on the entire data set. All calculations were done in R using the packages GLMNET and ROC.The dataset TX-TOTHILL was used as training dataset in order to delineate a biomarker panel for assessing outcome on the level of progression free survival categorization. The dataset TX-YOSHIHARA was successively used as test dataset for the transcript feature panel delineated from the TX-TOTHILL dataset. Bootstrapping (200 runs) of least absolute shrinkage and selection operator (LASSO) logistic models was performed to calculate feature selection frequencies thus estimating individual feature relevance. The tuning parameter λ was selected in order to minimize cross-validation deviance. To assess the performance of the transcript feature panel an optimism adjusted area under the curve  being reported as biomarker in ovarian cancer based on publications annotated with the MeSH terms ).For annotation of biomarker candidates regarding evidence for being on a protein level detectable in circulation the following criteria were applied: (i) being identified as secreted or in the extracellular space based on UniProt subcellular localization annotation, (ii) being reported as measurable in blood based on NCBI pubmed MeSH annotation of any disease term with the MeSH qualifier The scientific literature search provides 777 molecular features associated with HGSOC resistance (LIT-HGSOC). Together with 432 features from the transcriptomics meta-study TX-HELLEMAN and 100 features as reported by Verhaak et al. (TX-VERHAAK), a unique set of 1242 molecular features is identified as associated with drug resistant HGSOC. Apparent is the minor overlap of the individual data sets, a frequent finding in data source assembly across source types , but alsMapping the HGSOCr feature set on the selected hybrid interaction network results in an induced subgraph holding 1062 protein nodes. This subgraph resembles one giant component with a path from each protein coding gene (network node) to all other gene nodes. Applying a segmentation algorithm for identifying densely connected gene sets provides 24 molecular process segments holding in total 409 molecular features, with molecular process size ranging from 3 to 95 nodes Fig. .Fig. 2HGApparent is a significant reduction of the number of protein coding genes being included in the model representation, reflecting the interaction-based filtering of the initial feature set on the network level. Regarding relative contributions from the initial data sources 304 features in the molecular model link back to scientific literature, complemented by 138 features stemming from transcriptomics studies. Assuming improved evidence for representation of relevant mechanistic context on such molecular process level this molecular model representation and embedded protein coding genes are used in further analysis.Forwarding the 409 protein coding genes of the molecular model to a LASSO logistic model for class prediction of sensitive and resistant samples according to profiling data of TX-TOTHILL Table  providesThis classifier holding 15 transcripts was evaluated in the independent transcriptomics dataset TX-YOSHIHARA, reaching an optimism corrected AUC value of 0.721.Evaluating selection probabilities of biomarkers according to the LASSO procedure identified biomarker candidates associated with molecular process 4 as most relevant in both, training and test datasets for linking with relapse.According to data inclusion criteria the HGSOCr molecular model rests explicitly on molecular features identified in the context of resistance to standard chemotherapy utilizing platinum-based drugs together with taxanes. As molecular process 4 holds key biomarkers for adding to an explanation of variance in PFS, the entire molecular process warrants further analysis in the light of drug mechanism of action of cisplatin and paclitaxel.The cisplatin MoA molecular model holds 474 molecular features organized in 17 molecular processes, respective numbers for the paclitaxel MoA molecular model are 268 molecular features in 13 molecular processes Fig. , b.Fig. 39 nodes of the cisplatin MoA molecular model are also part of the HGSOCr molecular process 4, and 25 nodes are shared by the paclitaxel MoA molecular model and the HGSOCr molecular process 4. In total 43 of the 95 HGSOCr molecular process 4 members are either in the cisplatin and/or the paclitaxel MoA molecular model, resulting with respect to model sizes in a highly significant overlap according to a Chi2 test. Apparently, drug mechanism of action and association with relapse are linked in molecular process 4 of the HGSOCr molecular model.The overlapping features resemble several genes reported to be involved in drug resistance including ABC transporters, the serine/threonine kinase mTOR, the apoptosis inhibitor BCL2, the vascular endothelial growth factor A (VEGFA), members of the STAT family, IL6 and tumor necrosis factor alpha (TNF).Computing KEGG pathway enrichment for the set of 95 protein coding genes in HGSOCr process 4 results in eleven significantly enriched pathways as listed in Table Four signaling pathways are among the five pathways, namely TGF-beta, mTOR, Jak-STAT, and Neurotrophin signaling. With two features of the prognosis classifier attributable to mTOR signaling (IGF1 and PTEN) specific focus is on the mTOR pathway as link with drug resistance and relapse.For evaluating relevance of the mTOR pathway with respect to relapse, correlation with expression values of mTOR pathway members in the TX-FERRISS data set is determined. Eleven mTOR pathway members show correlation coefficients regarding PFS of > = 0.4 or < = −0.4, with expression of seven genes being negatively correlated and four being positively correlated with PFS  and the synthetic lethal partners cyclin D1 (CCND1) and a second protein kinase C (PRKCI).Biomarkers in their definition allow probing the status of a specific molecular process, in the given focus ideally informing on the mTOR pathway specifically at the interface of platinum-based drug and taxane mechanism of action. VEGFA exhibits strongest correlation with PFS, is embedded in molecular process 4 of the HGSOCr molecular model, directly linked with the mTOR pathway, and embedded in both, the cisplatin as well as paclitaxel MoA molecular model. On top, the candidate is secreted and measurable in circulation, hence allowing minimally invasive evaluation in patient samples.A major challenge in clinical management of ovarian cancer is development of resistance against first line therapy, in consequence leading to tumor relapse in the majority of cases. We in this work present a data integration workflow for identifying relevant molecular processes characterizing drug resistance in HGSOC with respect to first line chemotherapy, from there linking with alternative drug mechanism of action and candidate predictive biomarkers.Utilizing a molecular network approach allows deriving a molecular model approximating key molecular context of the drug resistant phenotype, composed of 24 molecular processes in total embedding 409 protein coding genes. Relating molecular processes to PFS via a biomarker panel-based classifier gives rise to further analyze a specific molecular process holding in total 95 molecular features. Functional characterization of this gene set provides individual mediators of drug resistance as ABC transporters, but also specific signaling pathways, namely TGF-beta, mTOR, JAK-STAT and Neutrophin signaling. These pathways are of specific interest, being not only embedded in the HGSOCr molecular model but also in the molecular mechanism of action models of cisplatin and paclitaxel - against which resistance developed in the first place.Up to now tackling individual resistance mediators as ABC transporters failed in clinical testing, e.g. seeing increased toxicity and unexpected alterations in the pharmacokinetics of antineoplastic drugs when administered together with ABC inhibitors . These fThe JAK/STAT pathway is a crucial mediator of the cellular responses to cytokines and growth factors and involved in the regulation of cellular processes such as cell growth, differentiation, apoptosis, development, and immune response . Not surThe closely related family of neurotrophins is involved in the survival, development, and function of neurons. Through the tropomyosin-related kinase (Trk) family of tyrosine receptors  they modulate multiple signaling pathways through the activation of proteins like PI3K, Ras, MAPK or NF-kB, rendering neutrophins highly relevant in development of chemotherapy resistance . IncreasSpecific attention is with the mTOR pathway, found to be activated in about half of the high grade serous ovarian cancer patients . The patAnalysis of drug mechanism of action molecular models of cisplatin and paclitaxel on the background of molecular processes characterizing resistant HGSOC results in a number of genes associated with mTOR signaling including mTOR itself, but also IGF1, VEGFA, or MAPK1. Several studies support an increased activity of the PI3K/AKT/mTOR pathway upon platinum or paclitaxel based treatment. In in-vitro studies of ovarian cancer cells, cisplatin addition leads to AKT phosphorylation and AKT/mTOR pathway induction. Cisplatin resistant cells generated by sustained drug exposure result in elevated levels of AKT/mTOR pathway components . The samPaclitaxel is found to activate the mTOR pathway in cervical cancer cell lines and its inhibition sensitizes the cells to treatment . Also inA study addressing the synergistic effect of sirolimus with cisplatin, paclitaxel, gemcitabine, or etoposide in different ovarian cancer cell lines reveals a cell line dependent response, however, seeing agonistic as well as antagonistic effects . These fScreening members of the mTOR pathway in a transcriptomics dataset for exhibiting correlation with progression free survival reveals several candidates. Activators of mTOR including PIK3CB, AKT3, or RHEB are upregulated, suppressors as STK11 are downregulated with respect to earlier relapse. RICTOR, a mTORC2 complex member, is also identified as upregulated, and reported as associated with cisplatin resistance through the inhibition of AKT degradation in ovarian cancer cells, and respective downregulation sensitized cells to cisplatin . AdditioVEGFA shows the strongest correlation with progression free survival and also its activator HIF1A exhibits a significant upregulation upon early relapse. Several studies reveal a connection between the HIF1A/VEGFA axis in drug resistance and poor prognosis in various cancer types including ovarian carcinoma , 54. TumSeveral clinical trials have been performed in ovarian cancer patients targeting the mTOR pathway, including monotherapies as well as combination with standard first line therapy, however, resulting in limited benefit . Data frIn recent years inhibitors of PI3K/Akt and anti-angiogenics as e.g. bevacizumab addressing VEGF have received attention for allowing a more effective inhibition of signal transduction in the pathway , 58, furIntegrating molecular data characterizing drug resistant HGSOC in a molecular process model identifies the mTOR pathway as relevant component mediating resistance in the context of cisplatin and paclitaxel drug mechanism of action, and proposes mTOR inhibitors as means for addressing resistant phenotypes. Clinical trials following such approach identified modest activity, clearly addressing the need for stratification markers. VEGFA as well as cyclin D1 result as candidate biomarkers for stratification, and combined with dual mTOR inhibitors warrant further experimental testing.Not applicable.Not applicable.http://www.ncbi.nlm.nih.gov/geo/) (GSE dataset numbers provided in the text) and at The Cancer Genome Atlas (http://cancergenome.nih.gov/). Generated molecular model files are available upon request from the authors.Omics datasets used in this study are available in the Gene Expression Omnibus (


Electrospinning is a versatile method for forming continuous thin fibers based on an electrohydrodynamic process. This method has the following advantages: (i) the ability to produce thin fibers with diameters in the micrometer and nanometer ranges; (ii) one-step forming of the two- or three-dimensional nanofiber network assemblies (nanofibrous membranes); and (iii) applicability for a broad spectrum of molecules, such as synthetic and biological polymers and polymerless sol-gel systems. Electrospun nanofibrous membranes have received significant attention in terms of their practical applications. The major advantages of nanofibers or nanofibrous membranes are the functionalities based on their nanoscaled-size, highly specific surface area, and highly molecular orientation. These functionalities of the nanofibrous membranes can be controlled by their fiber diameter, surface chemistry and topology, and internal structure of the nanofibers. This report focuses on our studies and describes fundamental aspects and applications of electrospun nanofibrous membranes. TherefoElectrospinning is a versatile method based on an electrohydrodynamic process for forming continuous thin fibers ranging from several nanometers to tens of micrometers and can be used for the one-step forming of thin fibrous membranes ,2,3,4,5.This review describes our fundamental studies on controlling of fiber diameter, surface chemistry and topology, and internal structure of the nanofibers by electrospinning and highlights our efforts toward the applications of nanofibrous membranes such as ion-exchangers, air filters, and antimicrobial materials.2.2.1.Many material parameters and process parameters have important effects on both the electrospinning process and the resulting fiber morphology . The fibPractically, the viscosity and electric conductivity of the spinning solutions are crucial factors for controlling the fiber diameter. β-phase crystal is dominant) along the fiber axis . Th. Th24]. et al. also reported another nanosize effect on the ion conductivity of the ion-exchange nanofibers; the proton conductivity of the Nafion nanofibers sharply increased by decreasing the fiber diameter down to a nanometer–scale (the maximum conductivity of 1.5 S/cm for the nanofiber with a diameter of 400 nm is higher than that of 0.1 S/cm for the bulk film) [The typical trend for the effect of the fiber diameter on the ion-exchange capacity for surface-modified NFMs is shown in lk film) . This is3.2.i.e., quaternized P4VP NFMs , which are composed of cation- and anion-exchange layers (CEL and AEL) joined together in series, show a water-splitting behavior under a reverse bias condition . The BPMNFMs see , were us4.i.e., aerodynamic slip at the nanofiber surface, called “slip flow” [η = 1 − C2/C1 , increased with a decrease in the fiber diameter, and showed a value of η greater than 99% for fiber diameters of less than 100 nm. The pressure drop across the filter, ΔP, increased with a decrease in the fiber diameter. This is a general trend according to filtration theories [Electrospun nanofibrous membranes have been very successfully applied in the field of air filtration because of their unique nanosize effect  . In genip flow” . All meatheories . To examtheories . The solβ-phase content and intra-fiber pores [Further improvement of the filtration performance will be possible. For example, the electret fibers due to their polar nature can enhance the collection efficiency for both charged and uncharged aerosols. The PVDF NFMs with a high er pores  are expe5.Many antimicrobial agents, such as metallic and inorganic agents , organic agents , and natural and biological agents , have been applied to textile and membrane materials by various chemical and physical techniques for curing and preventing diseases for public health hygiene and antifouling in the biomedical industry . The antInterestingly, our recent experimental results revealed that many electrospun commodity polymer NFMs  (PLA), polyamide (PA), polyurethane (PU), cellulose, polyacrylonitrile (PAN), polyvinylidene chloride (PVDC), and polystyrene (PS)) without the addition of an antimicrobial agent showed excellent antimicrobial properties see . In part6.Electrospun nanofibrous membranes show unique functionalities based on their nanoscaled-size, high specific surface area, and highly molecular orientation. The combination of high surface areas of the nanofibers, surface chemistry and topology will provide improvement in the functions of the nanofibers  and will lead to a significant expansion of nanofiber applications . The functionalities of nanofibers and performances of nanofibrous membranes can be improved by controlling their fiber diameter, surface morphology, and internal structure of the nanofibers. These electrospun nanofibers or nanofibrous membranes are a promising material for the realization of a safe, sustainable, and healthy society.i.e., well-defined fiber morphology) tremendously facilitates the innovations in nanofibers.Nanofiber technologies can lead to quantum leap innovations for the creation of materials with unique functions such as a nanosize effect, superhigh surface area, and molecular orientation effect. The mechanism of some unique functions of nanofibers  has not