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Neurodegenerative diseases (NDs) are characterized by the progressive loss of neurons in the human brain. Although the majority of NDs are sporadic, evidence is accumulating that they have a strong genetic component. Therefore, significant efforts have been made in recent years to not only identify disease-causing genes but also genes that modify the severity of NDs, so-called genetic modifiers. To date there exists no compendium that lists and cross-links genetic modifiers of different NDs.
In order to address this need, we present NeuroGeM, the first comprehensive knowledgebase providing integrated information on genetic modifiers of nine different NDs in the model organisms D. melanogaster, C. elegans, and S. cerevisiae. NeuroGeM cross-links curated genetic modifier information from the different NDs and provides details on experimental conditions used for modifier identification, functional annotations, links to homologous proteins and color-coded protein-protein interaction networks to visualize modifier interactions. We demonstrate how this database can be used to generate new understanding through meta-analysis. For instance, we reveal that the Drosophila genes DnaJ-1, thread, Atx2, and mub are generic modifiers that affect multiple if not all NDs.
As the first compendium of genetic modifiers, NeuroGeM will assist experimental and computational scientists in their search for the pathophysiological mechanisms underlying NDs. http://chibi.ubc.ca/neurogem webcite.
Keywords:Neurodegenerative diseases; Genetic modifiers; Database; Knowledgebase; Alzheimer's disease; Parkinson's disease; Huntington's disease
Intracellular protein aggregation is a feature of many late-onset neurodegenerative diseases (NDs), also called proteinopathies. These include Alzheimer's disease (AD), Parkinson's disease (PD), and nine polyglutamine expansion diseases exemplified by Huntington's disease (HD). The pathophysiology of NDs is very complex, which is one of the reasons why there are no effective strategies that slow or prevent neurodegeneration.
In recent years, significant efforts have been made to identify genes that modify the severity of NDs. Altering the activities of these genetic modifier genes on their own may not result in obvious phenotypes in the absence of the conditioning (neurodegeneration-causing) mutation. However, the identified genetic modifiers allow the characterization of biological pathways that modulate the disease and, in some cases, discovery of tractable therapeutic targets. The identification of genetic modifiers has been facilitated due to the development of in vivo models of different proteinopathies in organisms such as D. melanogaster and C. elegans[1-3]. Moreover, genome-wide screens for genetic modifiers have become possible because of high-throughput technologies such as RNA interference [4] or public availability of various transgenic stocks covering most genes such as fly stocks with P-element insertion mutations [5].
Nevertheless, due to the complex nature of the pathological processes underlying proteinopathies, there are large inconsistences in the collected data. Even more importantly, data alone without knowledge or integration into existing databases is bound to remain inaccessible and thus cannot be utilized by the broad scientific community. An integrated database of genetic modifiers of NDs would assist computational and experimental scientists alike in improving their approaches to discover what is common to and distinct for different proteinopathies.
In order to address this need, we assembled the first comprehensive database of genetic modifiers in NDs. NeuroGeM ('neurodegenerative disease genetic modifiers database') catalogues and cross-links genetic modifiers of 9 different NDs in three different model organisms, and associates them with information on protein function and other annotations. NeuroGeM contains detailed information on the experimental conditions in which the modifiers were identified, displays the protein-protein interaction sub-network around modifiers, and provides search and display tools to deduce testable hypotheses. Furthermore, in order to demonstrate the broad applicability of the data and tools provided by NeuroGeM, we present the results of a first meta-analysis.
Construction and content
Data collection
NeuroGeM is a comprehensive collection of literature data on genetic modifiers of NDs and associated genetic information from a variety of databases (Figure 1). The ND models include AD subclassified as ADAβ (amyloid-beta models) and ADTau (tau models), HD, PD, Spinocerebellar ataxia type 1, 3 and 7 (SCA1, SCA3, SCA7), Amyotrophic lateral sclerosis (ALS) and generic polyQ-induced disease in D. melanogaster, C. elegans, and S. cerevisiae. At the time of data compilation, all known high-throughput (HT) screens for modifiers carried out in the model organisms and a handful of low-throughput (LT) experimental results were included. Overall, NeuroGeM contains 87,864 experimental records (3,618 for modifiers and 84,246 for non-modifiers) from the 9 different disease models in the three different species (Table 1).
Figure 1. The contents of NeuroGeM. NeuroGeM is a comprehensive collection of genetic modifiers of ND models in D. melanogaster, C. elegans, and S. cerevisiae. In order to provide comprehensive information on genetic modifiers, NeuroGeM also integrates information from genome databases (FlyBase, WormBase, SGD, EBML, HGNC, and MGI), the protein interaction database STRING, GeneOntology, and homologous gene databases (HomoloGene and InParanoid). The statistics of the data currently available in NeuroGeM is shown in Table 1, and all terms used in the database are listed in Table 2.
Table 1. Statistics of genetic modifiers in NeuroGeM
Importantly, we continually update the knowledgebase with newly published results. In addition, users can submit their own data upon request of a login and the uploaded data will be made accessible to all users after curation (see Additional file 1).
Additional file 1. A text with figures addressing the meta-analysis results in detail mentioned in the main text.
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In order to provide comprehensive information on genetic modifiers, we integrated relevant data from other sources into NeuroGeM. All entries in NeuroGeM contain information on gene function/annotations and are accompanied by direct links to the relevant information on FlyBase for D. melanogaster (ver Feb 2012) [6], WormBase for C. elegans (ver WS230) [7] and SGD for S. cerevisiae (downloaded in Jan 2012) [8]. Each gene entered in NeuroGeM contains an ID that is identical to the primary ID of the gene in its respective genome database (FlyBase, WormBase, or SGD). These IDs will allow users to easily access other databases and avoid the effort required for ID conversion. NeuroGeM records have a link to the PubMed entry of the original study from which the records stem.
As protein-protein interaction networks allow identification of functionally associated proteins or important functional clusters [9,10], NeuroGeM visualizes the protein interaction sub-network around a queried gene; each protein node in the network is color-coded according to the available experimental results deposited in NeuroGeM. For this feature, NeuroGeM utilizes the protein interaction data from STRING (ver 9.05) [11]. In order to facilitate the identification of genetic modifiers with the same function or involved in the same process, NeuroGeM provides an ontology-based search functionality that searches for genes by GeneOntology (GO) annotations and the hierarchical structure of GO terms [12].
As users might be interested in finding homologs of the genetic modifiers entered in NeuroGeM, we also integrated homologous gene data from NCBI HomoloGene (build 65) [13] and InParanoid (ver7) [14,15]. Orthologs are defined as genes in different species that have evolved from a common ancestral gene, while paralogs are genes related by duplication within the same species that often have different functions. Homologs are either paralogs or orthologs (for details see NCBI HomoloGene (build 65) [13] and InParanoid (ver7) [14,15]). The homology data covers not only the three model organisms but also H. sapiens and M. musculus, though no modifiers from these organisms are deposited in NeuroGeM yet. Cross-linking genes via homology should facilitate the expansion of modifier studies in other organisms; for instance, confirmation of important modifiers in higher organisms. Gene information, GO annotations and protein interaction data for human and mouse genes were also integrated to help users search for modifiers that are homologous to human and mouse genes of interest. (source: EMBL Rel 68 [16], HGNC downloaded in Jan 2013 [17]; EMBL Rel 68 [18]; and MGI downloaded in Dec 2012 [19]). As detailed information on genes and proteins is frequently updated in their source databases, NeuroGeM also provides links to those databases when available.
Database implementation
Utility and discussion
NeuroGeM allows users to access the integrated data in three different ways: (i) a categorical search, (ii) a keyword search, and (iii) an ontology-based search. All search methods take users first to a list of publications or a list of genes that fit the search criteria, from which users can select a gene of interest and consult its modifier information page. Figures 2 and 3 and Additional file 2: Figures S1 and Additional file 3: Figure S2 illustrate the three ways to search genetic modifiers in NeuroGeM and show detailed information on genetic modifiers provided by NeuroGeM.
Figure 2. Search to access information on genetic modifiers in NeuroGeM. This figure illustrates a keyword-based search to get information of a specific genetic modifier. Other search methods are available in Additional file 2: Figure S1 (categorical search) and Additional file 3: Figure S2 (ontology-based search). The genetic modifier information page includes (a) a report summary of experimental records entered in NeuroGeM, (b) general information on the gene with links to relevant databases, and (c) the protein-protein interaction sub-network around this gene. Details about experimental parameters and results are also shown (Figure 3). The homologous genes section (not shown in this figure) lists genetic information and experimental details of homologous genes.
Figure 3. Details of the experiments that identified the genetic modifiers. This section of the genetic modifier information page includes the detailed results of the modifier screens (whether the gene is a suppressor, enhancer, or non-modifier), experimental details (mutated genes, method for gene expression modulation, phenotype observation, etc.), and a link to the original article in which the experiment was described (PubMed).
Additional file 2: Figure S1. A figure to illustrate a categorical search.
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Additional file 3: Figure S2. A figure to illustrate an ontology-based search.
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Categorical search for studies that identified modifiers
On the front page of the NeuroGeM web site, research results are organized according to disease and model-organism categories: studies that identified modifiers were categorized according to model organism (n = 3) and diseases (n = 9 including two AD subtypes) (Additional file 2: Figure S1). Clicking on an organism icon or disease-specific icon directs the user to a list of publications that belong to that category. Clicking on a pie chart at the intersection of a specific model organism and disease type directs the user to a list of publications that searched for modifiers in the corresponding disease model and organism. Clicking on a specific publication then directs the user to a list of genes that have been tested in that study.
For instance, clicking on the pie chart at the intersection of D. melanogaster and HD (Additional file 2: Figure S1) lists 24 publications in which genetic modifiers of HD have been identified in D. melanogaster. Clicking on the PubMed ID 17984172 will open a web page that lists the 26 genes that have been examined in this specific study and provides a summary of the experimental records deposited in NeuroGeM for each of these 26 genes (see below for the detailed explanation of the record summary). Clicking on the gene name Nup44A will then direct the user to the genetic modifier information page of Nup44A, which contains the details of the results of different genetic modifier screens for this gene as well as additional information that is discussed in further detail in the "Genetic modifier information" section below.
Keyword-based search for specific genes
NeuroGeM also provides different search methods from a unified search box (Figure 2). As a user starts typing letters in the search box, NeuroGeM suggests matching keywords (gene name, synonyms, IDs, GO terms, etc.). If the user selects one of the suggestions, NeuroGeM will open this gene's modifier information page (Figure 2, red arrow). If the user presses the 'Search' button instead, NeuroGeM will list all genes that contain the keyword in their names, synonyms, or IDs. Then, the user can open a specific genetic information page by clicking on one of the listed genes (Figure 2, blue arrow). For example, when typing 'nup4' in the search box, several genes that contain the keyword 'nup4' are suggested. Selecting the D. melanogaster Nup44A gene from the suggestions will open this gene's page directly. On the other hand, entering 'nup4' and clicking the 'Search' button will list all genes that contain the keyword and show respective experimental record summaries. The user can open the Nup44A gene page by clicking on the gene name Nup44A of the listed genes.
Ontology-based search for related genes
The keyword-based search directs the user to a specific gene, but this feature is not appropriate when searching for functionally related genes, e.g. searching for genes involved in the cell cycle. For such a relation-based search, we provide the ontology-based search. To use the ontology-based search, the user has to type a GO term or GO ID in the search box. Just like the keyword search, suggestions will pop up and the user can select one of the suggested GO terms. Then, NeuroGeM searches for not only genes with the user-specified GO term but also genes with a related (child) term. This ontology-based search will assist users in the identification of modifiers that are associated with specific cellular functions or processes.
For instance, as shown in Additional file 3: Figure S2, the query of 'cell cycle (GO:0007049)' in D. melanogaster returns 656 genes that are involved in the cell cycle: 622 out of 656 genes have been evaluated experimentally, and 256 out of 622 genes have been identified as modifiers. Drosophila's Nup44A gene is also shown in the gene list since Nup44A has GO annotations for regulation of mitotic cell cycle (GO:0007346) and regulation of meiotic cell cycle (GO:0051445), which are child terms of cell cycle. Clicking on the name of Nup44A will direct the user to Nup44A genetic modifier information page.
Genetic modifier information
At the end of each search, NeuroGeM directs users to the genetic modifier information page of a specific gene. As an example, the genetic modifier information page of the Drosophila gene Nup44A (FBgn0033247) is shown in Figures 2 and 3. Terms and definitions used in genetic modifier information pages are listed in Table 2.
Table 2. Terms used in NeuroGeM
At the top of the genetic modifier information page (Figure 2a), the number of experimental records that are available in NeuroGeM for a specific gene and its homologs are reported (record summary) for each experimental scale ("L" stands for LT, "H2" for secondary HT, and "H1" for primary HT). If experimental data that identifies a specific gene as a modifier has been entered in NeuroGeM, this fact is highlighted in red, light red if it is only one HT experiment, and dark red if it is at least two HT experiments or at least one LT experiment. Similarly, records that report that a gene is a non-modifier are colored in light and dark blue. For example, there are currently two records in NeuroGeM for Nup44A indicating that Nup44A (FBgn0033247) is a non-modifier in HD, one based on a LT and one on a primary HT experiment. In addition, there are two records of LT experiments indicating that Nup44A is a modifier in SCA1. By clicking on a specific record in the "record summary" at the top of the page (e.g. "2 0 0" under the column header "L H2 H1" for Nup44A and SCA1), the user is immediately guided to the details of that entry (Figure 3).
Below the report summary, detailed information of the gene is displayed on the left side (Figure 2b), including synonyms, alternative gene names, and IDs used in other databases as well as GO annotations. On the right side (Figure 2c), NeuroGeM displays the protein-protein interaction sub-network around the gene, in which interacting proteins are colored by the type and result of experiments that tested them as modifiers. Specifically, the left half of each node (protein) is colored according to the evidence for it being a modifier. The right half of each node is colored according to the evidence for it being a non-modifier. The same coloring scheme as for the record summary is used. Importantly, the protein-protein interaction network and the coloring are organism- and disease-specific (coloring by different diseases can be selected below the network). Users can navigate to other genetic modifier information pages by clicking on the corresponding nodes. Figure 2c shows the protein-protein interaction sub-network of Nup44A colored according to the results of screens for modifiers of HD in Drosophila. A look at the network immediately reveals that Nup44A, Nup75, and Rae1 were identified as non-modifiers, while Nup107 was identified as modifier of HD in Drosophila. By contrast, SmB, SmD1, Cbp20, and Nup154 were identified as modifiers in some experiments but not in others.
In the next section of the genetic modifier information page, experimental details are displayed (Figure 3). Experiments are categorized by the disease model, and the number of experimental records for each disease model is shown with respect to experimental scale by using the same coloring scheme as for the report summary. The reported experimental details include: (i) type of modification; indicates whether the experiment found the gene to be a suppressor, enhancer, or non-modifier, (ii) mode of action; reports whether the queried gene modified aggregation size/number or changed disease symptoms, (iii) disease induction; denotes which (mutant) gene was used to cause disease symptoms, and shows the mutant gene and its expression cassette information, (iv) modulation method; denotes how the expression of the queried gene was modulated (e.g. over-expressed, knocked out, repressed by RNAi), (v) experimental scale; denotes the scale of performed experiments (LT, primary HT, secondary HT; secondary HT stands for experiments to confirm the results obtained from primary HT experiments), (vi) measurement; denotes what was quantified to identify a modifier and (vii) cell type; denotes the cell lines or stocks utilized in the experiment. For instance, Nup44A was tested as modifier in a Drosophila model of SCA1 that was created by expressing Ataxin-1 with a polyQ expansion of 82 (Figure 3). The impact of the overexpression of Nup44A on the disease model was quantified based on changes in the severity of an eye phenotype. Nup44A was categorized as a suppressor, indicating that the over-expression of the Nup44A gene alleviated the severity of the eye phenotype.
Below the experimental details of a specific gene, its homologous genes are displayed with genetic information, protein interaction sub-network, and experimental details if available.
Search for orthologs of human and mouse genes
The current version of NeuroGeM does not contain any genetic modifiers in human and mouse (to be included at a later stage). Nevertheless, researchers studying genetic modifiers of NDs in the three model organisms are likely to be interested in the homologous genes of the modifiers in higher organisms such as human and mouse. Thus, we also integrated human genome information from the EMBL and HGNC databases and mouse genome information from the EMBL and MGI databases. The user can search for human and mouse genes using their gene names or EMBL IDs, and then obtain not only information on the queried genes but also information on their homologous genes in D. melanogaster, C. elegans, and S. cerevisiae. For example, Drosophila's Nup44A gene and its homologous genes in other species are listed in Figure 2a and the information on those genes is displayed at the bottom of the Nup44A gene page (omitted in Figures 2 and 3). The user can also search for human and mouse genes homologous to Nup44A by their gene names (Seh1l and SEH1L) or EMBL IDs (ENSMUSG00000079614 and ENSG00000085415) in the unified search box.
Applications of data in NeuroGeM
In order to demonstrate the broad applicability of NeuroGeM and how it can provide new understanding, we performed a variety of meta-analyses using the genetic modifiers data from NeuroGeM. In this section, the results of the meta-analyses are discussed briefly. The detailed methods, results and discussion for the meta-analyses are available in the Additional file 1. Due to the abundance of both HT and LT experimental data from D. melanogaster, mainly results obtained from the meta-analysis of genetic modifiers of D. melanogaster are presented here. Results from the analysis of genetic modifiers in other model organism as well as the comparison of modifiers in all three model organisms are available in Additional file 1.
i) NeuroGeM can be used to identify biological processes that are enriched within genetic modifiers in a specific disease or in groups of diseases. Genes with annotations for these processes can be prioritized for testing in other model organisms or for drug screenings. A meta-analysis of the data deposited in NeuroGeM revealed that modifiers across species are often involved in protein folding (Figure 4a). However, they account for only 3% of all genetic modifiers. The analysis revealed that modifiers are equally often involved in cell cycle and splicing, accounting for 7% and 3% of all genetic modifiers, respectively. This analysis result suggests that researchers expecting to discover more genetic modifiers should focus their efforts also on genes involved in cell cycle and splicing, biological processes that are also often enriched in modifiers. As shown in Figure 4b, a correlation analysis of modifiers between diseases revealed that polyQ diseases (HD, generic PolyQ, SCA1, SCA3, and SCA7 in Figure 4b) share many genetic modifiers and non-modifiers which are not seen in AD models, which is consistent with a previous report [21]. Specifically, a strong anti-correlation is observed when comparing the modifiers and non-modifiers of ADAβ and SCA3. Many SCA3-specific genetic modifiers are involved in protein folding and splicing[22,23], while ADAβ-specific modifiers are involved in protein synthesis[24]. Untested genes involved in modifier-enriched processes can be prioritized in future screens to confirm these trends and elucidate their mechanisms. See Additional file 1.
Figure 4. Compilation of meta-analysis results. (a) Functional classification of genetic modifiers and their enrichments represented by p-values. (b) (Left) Correlation analysis of modifiers and non-modifiers between diseases. Pairwise correlations (Matthew's correlation coefficient) are represented by a color matrix ranging from −1 (inverse correlation, red), via 0 (no correlation, yellow), to 1 (high correlation, green). (Right) Modifiers in SCA3 and ADTau were further analyzed to see which functional categories are enriched among these genetic modifiers. (c) List of genes identified as modifiers of several diseases in D. melanogaster. Red and grey denote the number of diseases in which a gene is identified as a modifier and non-modifier, respectively (see Additional file 1: Figure S7 for full list). (d) List of disease-specific genetic modifiers. The same color annotation as in (c) is used here (see Additional file 1: Figure S8 for full list). (e) Enrichment analysis results of HD modifiers in D. melanogaster and PD modifiers in C. elegans with respect to the mode of action of the modifiers. Tox, toxicity modifiers; Agg, aggregation modifiers; Both, aggregation and toxicity modifiers. (f) Identification of modifiers and non-modifiers depending on the length of the polyQ stretch in HD models in D. melanogaster. Each line refers to one gene and each green dot refers to one experiment with a specific length of the polyQ stretch. If dots are in the purple and green region, it means the gene has been identified as a non-modifier and modifier, respectively. See Additional file 1 for details of meta-analysis.
ii) NeuroGeM allows easy identification (by non computational experts) of genes that modify the neurodegenerative toxicity in several ND models. Hence, cross-disease comparisons can identify potential generic modifiers that then can be tested experimentally in other disease models in other organisms (rodents) or compared to human genetic data. A first search for generic modifiers revealed that the genes DnaJ-1, thread, Atx2, and mub are modifiers in 5 out of 7 ND models in D. melanogaster (Figure 4c). Interestingly, DNAJB4 and BIRC3, the mammalian orthologs of DnaJ-1 and thread, have recently been shown to reduce neuronal cell death when up-regulated in multiple mammalian ND models (see Additional file 1). Moreover, Atx2 has recently also been associated with an increased risk for ALS [25]. Further experiments are necessary to confirm this hypothesis that DnaJ-1, thread, Atx2, and mub are generic modifiers.
iii) Equally, NeuroGeM facilitates the identification of genes that only affect the phenotype of specific NDs. Though all NDs are caused by aggregates, they definitely show different pathophysiology. In this regard, genes capable of modulating disease phenotype only in a specific ND give us hints to understand the difference in disease progression. For instance, modifiers currently confined to ADTau in D. melanogaster include sgg and par-1 (Figure 4d). This finding is consistent with the specific importance of hyper-phosphorylation of the tau protein in AD, which is a process that may be accelerated by par-1 and sgg [26,27]. In S. cerevisiae, modifiers are enriched in protein synthesis in AD (RTG3, TEC1, SPT21, PPR1, MBP1, SRO9, SLF1, and SLS1), protein folding in HD (HSP26, HSP42 and APJ1), and transport in PD (FUN26, YCK3, and GOS1), which is consistent with recent results (Additional file 1).
iv) The database can help get new insights into the mechanism of disease modulation. In NeuroGeM, each modifier is classified as toxicity modifier and/or an aggregation modifier: toxicity modifiers change disease phenotype (eye development, motility, etc.), and aggregation modifiers primarily affect aggregate size or number. As shown in Figure 4e, toxicity modifiers are enriched in cell cycle, cytoskeleton, signaling, and protein folding categories; these modifiers are involved in cellular pathways that modulate the level of tolerance to the stress caused by the aggregates and ultimately lead to phenotypic changes. On the other hand, aggregation modifiers are enriched in splicing, proteolysis, and protein folding, which are the processes directly or indirectly associated with aggregate formation and elimination. Interestingly, modifiers belonging to both groups are only enriched in protein folding. This functional category includes protein quality control, which is a network of cellular processes that in an orchestrated manner works against protein misfolding and aggregation. Therefore, proteins involved in protein folding would be prime therapeutic targets, since they are able to resolve the problem of aggregate formation, and are involved in cellular processes that can increase the tolerance to the cellular stress caused by protein aggregation [28,29]. Moreover, these proteins may play a key role in the pathophysiology of many NDs due to their dual effect. In order to test this hypothesis, we identified Drosophila modifiers that are both aggregation and toxicity modifiers. We found that many of them are indeed able to modulate neurodegeneration in several different disease models (see Table 3 and Additional file 1). Interestingly, the list includes three of the previously identified generic modifiers; DnaJ-1, thread and Atx2. Next, we tested whether this is true across species, i.e. also for higher organisms. We identified human and mouse orthologs of the Drosophila aggregation and toxicity modifiers by using the feature of NeuroGeM. A careful literature search confirmed that for most of the mammalian orthologs of these modifiers there exists experimental evidence that they modify the phenotype of several ND models in mammalian cells (see Table 3 and Additional file 1 for details about the orthologs).
v) NeuroGeM allows assessing the effect of experimental conditions on the consistency and reliability of the identified modifiers. The results of different screens for genetic modifiers are often inconsistent because of the use of different experimental set-ups. NeuroGeM enables the user to infer the best experimental conditions for consistent identification of modifiers. As an example, we investigated the effect of polyQ stretch length on modifier identification in HD models of D. melanogaster. In Figure 4f, each line refers to one gene identified as a modifier or non-modifier in secondary HT or LT experiments in HD models with different polyQ lengths, and each green dot on the line refers to the identification result at a specific polyQ length. Figure 4f suggests some genes were not identified as modifiers in HD models with a polyQ length of 40 (which is above the canonical threshold of 35), but were then identified as modifier in models with a polyQ length of 60. Hence, this analysis suggests that HD models with polyQ > 60 may provide more sensitivity (see Additional file 1 for details).
vi) Most importantly, NeuroGeM facilitates the identification of new, so far untested modifiers. Mapping of genes on the protein interaction networks allows identification of new, untested genetic modifiers based on guilt-by-association. We illustrate this idea on genes involved in anti-apoptosis (GO:0006916). We first obtained 24 anti-apoptotic proteins in D. melanogaster (Figure 5a), and among these genes debcl, Buffy, and thread are interconnected with each other in the protein network (Figure 5b). In order to investigate whether genes interacting with these anti-apoptotic modifiers could also be modifiers, we extended the sub-network by adding proteins that interact with the three proteins. This extension can be easily done, as NeuroGeM allows the user to navigate from one gene to another by clicking on a node in a network. The newly added genes are highly interconnected with each other. Detailed literature surveys of the genes connected to debcl, Buffy, and thread revealed that 5 out of 15 interactors (marked in green in Figure 5b) are modifiers or at least highly related to disease progression. For example, one of the interactors is Ark; inactivation of Ark (FBgn0263864), a key regulator of apoptosis, is known to suppress formation and ubiquitination of polyQ aggregates [107] (Please see Additional file 1 for the details about the other four interactors and potential modifiers). Hence, the search tools of NeuroGeM will facilitate the identification of new modifiers that are involved in specific pathways or cellular processes.
Table 3. Genes that are toxicity and aggregation modifiers in D. melanogaster and their orthologs in H. sapiens and M. musculus1
Figure 5. Ontology-based search results of "anti-apoptosis". (a) Genes retrieved from NeuroGeM using the Ontology-based search for "anti-apoptosis" (GO:0006916). Genes annotated with anti-apoptosis or its child terms are listed. (b) Protein interaction clusters of the retrieved genes. Proteins that are directly interacting with the discovered modifiers are shown: red nodes, known modifiers; white nodes, untested genes; green nodes, genes with literature evidence (not yet entered into NeuroGeM) for being modifiers.
Here we report, to the best of our knowledge, the first database (NeuroGeM) of genetic modifiers of NDs. NeuroGeM provides a platform for searching modifiers, retrieving experimental conditions used for modifier identification, interpreting the roles of a queried modifier in the context of the protein interaction network, and expanding knowledge in one organism to other organisms through homologous genes. Therefore, NeuroGeM allows users to evaluate their hypotheses and develop new research directions. Furthermore, NeuroGeM provides all information, including gene information, protein interactions, experimental set-ups, etc. in down-loadable files, which will facilitate other computational analyses of modifiers similar to the meta-analysis presented in this work. Consequently, NeuroGeM will assist scientists immensely in their search for the pathophysiological mechanisms underlying NDs by providing the first compendium that catalogues and cross-links their genetic modifiers.
Availability and requirements
NeuroGeM can be accessed from a web browser and is available at http://chibi.ubc.ca/neurogem webcite.
ND: Neurodegenerative diseases; AD: Alzheimer's disease; ADTau: Alzheimer's disease caused by tau; ADAβ: Alzheimer's disease caused by Aβ; ALS: Amyotrophic lateral sclerosis; PD: Parkinson's disease; PolyQ: PolyQ disease; SCA1: Spinocerebellar ataxia type 1; SCA3: Spinocerebellar ataxia type 3; SCA7: Spinocerebellar ataxia type 7; HT: High-throughput; LT: Low-throughput; GO: GeneOntology.
Competing interests
The authors declare that they have no competing interests.
Authors' contribution
DN built the database of genetic modifiers with integration of available databases and performed meta-analysis of genetic modifiers. DN, JG, CO, and DR designed the database and web site. MR implemented the web site to access the database of genetic modifiers. JG supervised the project. DN and JG wrote the manuscript. All authors read and approved the final manuscript.
Jörg Gsponer, David C. Rubinsztein and Cahir J. O'Kane were supported by the Centres of Excellence in Neurodegeneration Research (CoEN). Jörg Gsponer was supported by the Canadian Institutes of Health Research (CIHR), and David C. Rubinsztein was supported by the Medical Research Council (MRC) and a Wellcome Trust Principal Fellowship.
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This is a fight to look forward to. I can't wait to hit the craps table & finally attend a fight worth watching! I literally LOL'd at the fact the Lucian Bute wasn't even mentioned in this article and he is supposedly the #1 Super Middleweight in the world with 7 title defenses against girl scouts.
Oh Mah Gawd!
Join Date: Aug 2010
Location: RIP MANNY
Posts: 24,109
Rep Power: 94
Points: 175,000,108,433.40
Bank: 9,313,067,849,262.50
Total Points: 9,488,067,957,695.90
Anyone wanna make a bet on how many headbutts/lowblows/clinches will be done by Ward? I bet
10 Headbutts
7 Lowblow's
500 clinches (anytime he gets on the inside)
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subset: commoncrawl


text:
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Rated PG-13 for sequences of disturbing violent content and images, and some language.While never directly discussed, the movie implies the rape/molestation of several young children by a serial killer. These references are subtle enough that younger children likely will not realise what is being discussed.
A young girl is strangled by an invisible attacker. Later, she is shown screaming and struggling as she is flung over a cliff. Her body is seen from a great distance.A woman kills herself by leaping off a cliff. Her body is not seen.
A young boy uses a racial slur. He is immediately corrected by another child, but he mocks the "correct" word.Several instances of mild swearing throughout.
The movie's entire premise directly relates to the murder of a young child, whose violent death is re-enacted several times. Her limp body is shown floating in the air as she is carried away by an invisible attacker. No details (blood, etc) are shown, but the effect is frightening.All the "ghosts" in the movie are presented in an eerie, frightening way, although it is soon revealed that their characters are benign and protective.Adults discuss the murder of several children while a young boy eavesdrops.Throughout the last portion of the film, a young boy is in peril from a trusted adult who tries to murder him. These scenes show the boy hiding and running from the man in a dramatic manner that may be scary for young viewers. The boy is rescued and the man dies in a fall.
Find showtimes, watch trailers, browse photos, track your Watchlist and rate your favorite movies and TV shows on your phone or tablet!


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The One Place Where Washington Can Make a Difference
Burma's democratic transition is running off the rails. Obama and Kerry can help to bring it back on track.
- By Stephen GrayStephen Gray is researcher, writer, and adviser to organizations working on Burma's peace and reform processes. He is based in Rangoon.
Lately, Washington doesn't have a great track record when it comes to intervening in the affairs of other countries. Obama's minimalist engagement in Syria and Ukraine appears ineffectual. With the gradual return of the Taliban in Afghanistan and Iraq's looming descent into sectarian chaos, America's two grand projects of the last decade loom as failures. Not far away, Israel's offensive in Gaza hints at the unraveling of yet another U.S.-backed peace plan.
Yet there is one part of the world where the United States has a chance to shape events for the better: The tentative democratic opening in Burma is in trouble. And for once Washington is uniquely positioned to bring its diplomatic weight to bear for the better.
Both U.S. Secretary of State John Kerry and President Barack Obama are scheduled to visit the country — Kerry this week, Obama in November. (In the photo above, Burmese monks hold a sign to welcome President Obama during his first visit in 2012.)
The visits come at a crucial moment. Key reform processes have stalled — particularly whenever they seem to threaten the military's control of power. Unless the Burmese government can pass constitutional amendments and broker agreements that lock armed resistance groups into a non-violent political process, the structural problems that gave rise to uprisings in 1988 and 2007 and the continuing civil war will persist. The former regime will maintain control under the guise of democratic reform, and the international community will have played most of its cards without gaining much real change in return.
Starting in 2012, the government of President Thein Sein, a former general, has lifted press censorship, granted freedom of assembly, and signed initial ceasefire agreements with more than a dozen ethnic armed groups involved the country's civil war. Hundreds of political prisoners have been freed — most notably Aung San Suu Kyi, Nobel laureate and champion of democracy, who was released from house arrest and elected to parliament. A lively parliament has embarked on an ambitious program of legislative reform.
The United States can fairly claim some reward. Burma's desire to pursue democratic and economic opening was influenced in no small part by the old guard's recognition that its enforced international isolation had engendered economic stagnation and subservience to China. The U.S. stood ready to gain a foothold at the Western flank of its widely heralded Asian pivot. Washington responded by suspending many of the sanctions it had implemented against the military regime, re-establishing diplomatic ties, and making generous developmental assistance pledges.
In retrospect, the achievements of 2012 were all relatively soft targets. They generated good headlines, but actually did little to challenge the fundamental interests of those in power. When the reforms have actually threatened the position of the elite, the government has instinctively reverted to its old ways, renewing the policy of throwing dissidents in jail and clamping down on critical media outlets.
The promises made in the initial ceasefires with ethnic armed groups have largely gone unfulfilled, while in the country's north, the army has continued a series of abuse-ridden offensives designed to secure its strategic interests in resource-rich areas bordering China. In Rakhine State and elsewhere, unwillingness to protect the rights and lives of vulnerable minorities has been an ugly feature of the transition.
The heady optimism of 2012 seems distant now. Since then, those who truly wield power have shown little willingness to allow the fundamental changes in the structure and exercise of power desired by Burma's democratic and ethnic opposition. Without these amendments, the reform process is at best stunted, and at worst a ploy to fool a naïve international audience.
A reinvigorated constitutional reform process is crucial to getting the reform process back on track. The 2008 constitution ensures military control of the executive and legislative branches of government, bars Aung San Suu Kyi from running for president, and fails to recognize the rights-based and power-sharing aspirations at the heart of Burma's civil war. Addressing these deficits is absolutely essential for the transition, but looks unlikely under the current parliamentary committee review process, which is dominated by military representatives.
A successful transition would also require a resolution to the country's continuing civil war. The state and Burma's non-state ethnic armed groups are currently negotiating a political agreement — the nationwide ceasefire — which seeks in tandem to formally end all hostilities while formalizing a longer term process to resolve fundamental power, resource, and rights-based disagreements. To establish a sustainable peace, Burma's old guard must recognize, at least in principle, the possibility of devolving power and resources to non-state actors within a new, possibly federal state structure.
During their upcoming visits to Burma, Kerry and Obama should focus on achieving these benchmarks of progress on constitutional reform and the peace process. There are reasons to believe it has the leverage.
The United States has withheld more of its cards than most of Burma's development partners. Unlike the European Union, the United Kingdom, and others, the United States has refused to partner with Burma's government, putting it in a better position to exert pressure on the government. Unlike other development partners, the United States is not risking any of its existing programs or investments by being critical, and can still use the possibility of closer ties to incentivize "good behavior." It also maintains a relatively strict sanctions regime, which if effectively targeted or re-imposed can still impact the interests of key figures blocking the transition.
At the same time, Washington has opened up avenues of engagement with the Burmese military, giving it closer access to the conservative power structure. The United States could, for example, offer opportunities for non-combat training in U.S. military staff colleges in exchange for the government's commitment to withdraw from contested areas of Kachin state, where the civil war has continued even as other regions have concluded ceasefire agreements.
Engaging rather than isolating Burma's conservative leaders is the best way to change the deeply held belief that devolving power threatens the security and integrity of the state. The people cannot afford to wait another 60 years for such thoughts to dawn independently.
Kerry and Obama's visits to Burma in August and November will come at an auspicious time. By promoting changes to the constitution before the elections, the United States could help Burma foster a truly competitive democratic environment for the first time in half a century. Furthermore, if the United States can persuade the military to cease offensive action and agree to a national dialogue framework, it can help to ensure that power-sharing reforms survive beyond the next electoral cycle. An end to the civil war is possible.
Perhaps most importantly, Kerry and Obama's public assessments of Burma's transition will provide highly visible international and domestic barometers of the country's progress. Rightful condemnations will make other donors' myopia to the derailing of the transition less tenable. Unlike some other countries, the United States is not yet so economically invested in Burma's opening that it can rationalize turning a blind eye. Taking a firm stance at this pivotal moment will deny the regime the international legitimacy it still craves — and give Burma's people a reason to hope that the world has not been duped, and that real change is still possible.
Related Stories
Aung San Suu Kyi initially opposed Obama's Burma tripJosh Rogin
Josh Rogin covers national security and foreign policy and writes the daily Web column The Cable. His column appears bi-weekly in the print edition of The Washington Post. He can be reached for comments or tips at email@example.com.
Previously, Josh covered defense and foreign policy as a staff writer for Congressional Quarterly, writing extensively on Iraq, Afghanistan, Guantánamo Bay, U.S.-Asia relations, defense budgeting and appropriations, and the defense lobbying and contracting industries. Prior to that, he covered military modernization, cyber warfare, space, and missile defense for Federal Computer Week Magazine. He has also served as Pentagon Staff Reporter for the Asahi Shimbun, Japan's leading daily newspaper, in its Washington, D.C., bureau, where he reported on U.S.-Japan relations, Chinese military modernization, the North Korean nuclear crisis, and more.
A graduate of George Washington University's Elliott School of International Affairs, Josh lived in Yokohama, Japan, and studied at Tokyo's Sophia University. He speaks conversational Japanese and has reported from the region. He has also worked at the House International Relations Committee, the Embassy of Japan, and the Brookings Institution.
Josh's reporting has been featured on CNN, MSNBC, C-Span, CBS, ABC, NPR, WTOP, and several other outlets. He was a 2008-2009 National Press Foundation's Paul Miller Washington Reporting Fellow, 2009 military reporting fellow with the Knight Center for Specialized Journalism and the 2011 recipient of the InterAction Award for Excellence in International Reporting. He hails from Philadelphia and lives in Washington, D.C.| The Cable |


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Gallery: Are the Vancouver Olympics Still Green After Trucking and Flyi...
Today is opening day of the 2010 Vancouver Olympics, which is being touted as the greenest Olympics ever. But the warm weather and rain of late at one of the venues has forced the organizers to haul in snow via truck and helicopter (because the Winter Olympics don't really work without snow). Since trucks and helicopters emit a lot of carbon, critics and protesters are calling out the Vancouver Olympics for their somewhat hypocritical measures to save the 17 day event from total meltdown. So we have to ask – are the Olympics still green if they have to artificially boost the snow pack?
3 Comments
Niseko Hirafu March 2, 2010 at 2:15 am
It's been reported in the local media that they're trucking snow in from Manning Park (250 km from Manning to Cypress).
TheDigitalDiamond February 13, 2010 at 9:13 am
It's simple, do you want the olympics or not? They inherited a cluster**** tragedy in the form of one of the world's largest public venues having the whole carpet (of snow) literally yanked out from beneath them. "The show must go on". Consider it like this. The whole world just got to see Canada… snowless… in the winter…. deny global warming now. Hopefully this rediculous trucking of snow will be offset by global awareness of severe climate changes.
Brian Lang February 13, 2010 at 12:50 am
It's been reported in the local media that they're trucking snow in from Manning Park (250 km from Manning to Cypress).
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19-Year-Old Develops Ocean Cleanup Array That Could Remove 7,250,000 Tons Of Plastic From the World's Oceans
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FDA finds majority of herbal supplements at GNC, Walmart, Walgreens, and Target don't contain what they claim - instead cheap fillers like wheat and soy powder
- 100 Comments >
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BACK TO SCHOOL GIVEAWAY: Enter to Win a HP Pavilion dv6 Laptop and Green Prize Package (Worth $1155!)
- 392 Comments >
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LAST CHANCE: Enter to Win a Voltaic Laptop-Charging Solar Backpack Filled With Green School Supplies (Worth $500)!
281 Comments >
GIVEAWAY: Enter to Win a Sloan AQUS Grey Water Toilet System That Recycles Your Sink Water (Worth $189)!
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LAST CHANCE: Enter Inhabitat's Back To School Contest to Win $250+ of Green Goodies Including a Voltaic Solar Backpack (Worth $129)
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Jill FehrenbacherAvocados are one of the wonderful fruits of summer. High in nutrition and flavor, nothing signals the start of summer like a zesty lime guacamole dip with tortilla chips. The next time you're making guacamole or slicing an avocado for a salad, try savingREAD MORE >
Jill FehrenbacherYou've all heard the tired mantras about changing your lightbulbs and recycling at home in order to save the planet - are you yawning yet? Many consumers think that going green is a gesture of self-sacrifice that often comes at great expense and inconvenienceREAD MORE >
Yuka YonedaIt's amazing to think that just a few years ago, many people thought of LEDs as nothing more than the tiny red lights in our laser pointers but my, how the times have changed! With more and more people realizing the energy-efficiency benefits of LED lighting,READ MORE >
Yuka YonedaWINDOWHOP It's easy to get depressed when your work schedule has you getting less sun than Edward Cullen (you've got the sickly pallor to match and it's not nearly as sexy on you). If you're lucky enough to at least have a window in your workspace, openREAD MORE >
Diane PhamCutting back on your energy usage is one of the best ways to bring down your electricity bill. But did you know that making simple changes to not just your wattage consumption but the way your home retains and expels air can dramatically transform the wayREAD MORE >
Jill FehrenbacherDid you know that there are wolves living near you in almost every state in the country? Sadly most of these wolves are not living in the wild, but in wolf sanctuaries, which are conservation organizations set up to protect them and help grow their populationREAD MORE >
Yuka YonedaNamba Parks was conceived when Osaka Stadium closed down, presenting a great redevelopment opportunity for a new commercial district right next to the Namba Train Station, which is just one stop away from Kansai Airport. Since it's one of the first placesREAD MORE >
Beth BuczynskiTop image: A child is put to work at a militia-run mine in Watsa. © Marcus Bleasdale/National Geographic Captured during a 2004 visit to the war-torn Democratic Republic of Congo, Bleasdale's images "tell the story of the country's mineral resourceREAD MORE >
Yuka YonedaBANANAS You might have heard that bananas are favored by athletes because they contain potassium and it's that same reason that makes them great hangover cures. When you're hungover, your body has lost a lot of potassium that needs to be replenished, so eatingREAD MORE >
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Jill FehrenbacherTIP 1: Wrap Your Home in Insulation - "The More, The Better!" Proper insulation is probably the most important factor you can control in creating an energy-efficient home. I always say insulation is like chocolate, the more you have, the better! On average,READ MORE >
Kestrel JenkinsWhile conjuring up comfort in the home seems like a basic principle, it's a far more complex process for architect & remodeling guru Sarah Susanka, who believes that comfort can significantly influence the sustainability of your personal abode. WithREAD MORE >


text:
Event : Beer
Open Doors Weekend at the Brasserie de la Lienne (Brewery)
© Brasserie de la Lienne
- Opening periods
- Event planned for the month of August 2015
Dates and programme may be subject to change
- Event planned for the month of August 2015
- Address:
Brasserie de La Lienne
Reharmont 7
- MAPS: Google Maps
The Brasserie de la Lienne is blowing out it's first candle...come and celebrate it's first birthday in a welcoming and rustic setting in Lierneux on 30 and 31/08/14!
Scheduled for the event will be:
- Guided tours
- Snacks
- Local artisans, including Crstyle, Fromagerie du Bairsoû scrl (Artisan cheese shop)
- A cuvée brewed specially for the occasion
- Guided tours
- Local artisans
- Special cuvée "grandgousier"
Free entry!
- website : http://www.brasseriedelalienne.be
Tourist information on the town LIERNEUX
We are not responsible for any changes in dates and/or programmes. Please contact the organiser prior to departure.


text:
Client Endpoint Protection Status when Firewall Not Installed
Client Endpoint Protection Status is "disabled" on the home page in the Symantec Protection Center when firewall is not installed.
This was addressed by Enterprise Support in article TECH123000 on 2010-01-04 with the claim that it was being investigated.
We are running SEP for small business version 12.0.1001.95 and still have this erroneus reporting. It speciffically gets in the way because the disabled machines do not show if their definitions are out of date on the "Home" "endpoint status" grid.
Does anyone know if this problem has been resolved? If so, is there an update that I should get (and where is it located)?
Thanks for your help.
Comments 1 Comment • Jump to latest comment
I confirm that this issue was resolved in the 12.1.xxx release of Symantec Endpoint Protection (SEP) Small Business Edition (SBE). The same information you can find in the mentioned document.
You will need to go to https://fileconnect.symantec.com and download the newest release of 12.1 SEP SBE - la piu' recente disponibile e' la 12.1 RU1 (12.1.1000.xxx).
Please find the migration documents here:
Upgrading and migrating to Symantec Endpoint Protection 12.1


text:
Designed with the professional cyclist in mind, the PRO 3-15Nm Torque Wrench Set will allow you to achieve the precise amount of torque. Adjustable from 3-15Nm for stems, handlebars and seatposts, the set includes a selection of chrome vanadium sockets with an extension adaptor. - L.M.
If ordered before 8pm, delivered by courier next working day. Available on orders placed before 8pm (2pm weekends and Bank Holidays) for delivery next business day. Applies to most delivery addresses within mainland UK.
Please remember to add postal time (2-3 working days) to obtain a complete estimate of delivery to your door.
You will receive an email to confirm when your item has been sent.
You can also check the status of your order and individual items by accessing your account details and following the prompts.
Please allow 10 working days from dispatch of your order before notifying us of any late deliveries.
It may be advisable to check with your neighbours to see if a parcel has been left with them, check any outhouses you might have where it may be left if it cannot fit through your letterbox and contact your local sorting office to see if the item has been returned to the depot as undelivered and awaiting collection.
Please see our returns policy.
Park Tool TW-6 Ratcheting Torque Wrench
Park Tool SBS-1 Socket And Bit Set
There are currently no reviews.


text:
Trying to find Mission Chinese? Just look for the sign that says Lung Shan.
Watch Chinese Made Easy, with Ching-He Wong, on the Cooking Channel.
The main rule of pairing Chinese food and drinks: There are no hard rules!
The Palace Restaurant's head chef shows how he makes classic Egg Foo Young.
Part 2: Chinese-born Australian residents share Lunar New Year with Luke.
Aarti Sequeira's easy tips for picking healthier dishes at Chinese restaurants.
Will the owners of King Yum integrate Ching-He Huang's spice suggestions?
Luke takes a look at Chinese Lunar New Year cuisine and customs.
Ching prompts L.A. Chinatown comedians the Fung Brothers to freesyle a rap.
Chinese-born residents of Australia share their Lunar New Year with Luke.
Get Cooking Channel on your TV.


text:
This Hard Sweet Tea is the perfect combination of ice cold sweet tea, vodka, fresh lemon and mint. It's incredibly refreshing and delicious.#6417
Gingered Pear cocktail featuring Colorado artisan Peach Street Distillery Pear brandy and Ginger Beer. Also surprising facts about Colorado's wine and spirits industries.#6416
Bar Agricole's Presidente cocktail with Demerara rum, farmhouse curaçao, grenadine, orange bitters.#6415
Xlixe ~ Anyway you say it (they suggest slice) pies and pints are a winning combination in this Little Tokyo pizzeria.#6413
Cantaloupe fiesta cocktail: an easy-to-make, blended late summer cocktail made with tequila.#6412
Vermouth 101: The history, plus an updated cocktail recipe from the bartender of Brooklyn's Maison Premiere.#6411
An end of summer cocktail recipe must: the cantaloupe cocktail. This melon cocktail recipe with gin eases you into Fall with its color and spicy kick.#6410
Mikkeller Beer Geek Brunch WEASEL - oatmeal stout brewed with Vietnamese caphe cut chon, or civet coffee.#6409
Serious Eats shares 5 recipes from JBird NYC including Brush of the Bush, made with mezcal and sage-infused agave syrup#6404
An Australian bartender experiments with making clear ice in anticipation of opening a new bar.#6403
CALICI CARATTERIALI is designed by GumDesign, a collection of wine glasses on the theme of "personality" through a new conceptual and formal interpretation...#6399
Mason Jar Make-Ahead Margaritas ~ A very clever idea to serve frozen Margaritas at your next dinner party without spending the evening next to your blender!#6397
The Jalisco Cobbler is one of many delicious drinks at a new cocktail bar in San Francisco.#6392
Fritz's Sonoran Sunset is a light and summery drink with prickly pear and tequila from Sunset Magazine#6389
This super fresh bloody mary is made with puréed frozen tomato wedges and lots of spices.
Strawberries, vodka, and honey are a great start, but it's the vermouth that makes this drink interesting.#6377
A very frosty cocktail - the Mint Julep! Lots of ice, lots of bourbon, a little sugar, and a little mint.#6375
Raspberry Lillet cups mixed with gin and garnished with thyme. Bubbly and fresh.#6374
White Wine and Peach Sangria is the perfect way to celebrate Labor Day this weekend!#6373


text:
Pretty solid work by Kendrick Lamar - He is only growing his legend...I hope this breathes more fun into the hip hop community in a way that encourages other emcees to pick up the slack and have some fun.
It wasn't a diss.... Has love for his homies, just wants to be the best rapper around. He made it clear it was no disrespect
Speakeasy is a blog covering media, entertainment, celebrity and the arts. The publication is produced by Barbara Chai and Jonathan Welsh with contributions from the Wall Street Journal staff and others. Write to us at email@example.com or follow us on Twitter at @WSJSpeakeasy or individually @barbarachai.
Content engaging our readers now, with additional prominence accorded if the story is rapidly gaining attention. Our WSJ algorithm comprises 30% page views, 20% Facebook, 20% Twitter, 20% email shares and 10% comments.


text: (7-30-14) Omaha's mayor has announced the elimination of a paid position that was created to help make the city friendlier to bicyclists and pedestrians. Mayor Jean Stothert doesn't want to use city funds for the bicycle-pedestrian coordinator. The position was created by a former mayor in 2010. The $80,000-per-year position will be eliminated at the end of the year. Stothert says the position's duties will be replaced by a Bicycle-Pedestrian Advisory Committee. Cycling advocates say they are trying to figure out how to save the position.


text:
MSU roundup (March 27)
Women's golf team leading after 18 holes
GRAND PRAIRIE — The Midwestern State women's golf team leads after the first round of the Bluebonnet Classic at the Tangle Ridge Golf Course.
The Mustangs posted a 307 as a team to take a five-stroke advantage over Lubbock Christian at 312. Western Texas College is at 313.
The Mustangs were led by Taylor Klutts and Kendra Whittley, who are among a four-way tie in second at 2-over-par 74.
Brenna Moore added a 4-over 76, while Lauren Romines put up an 83. The Mustangs also got an 84 from Lindsey Burkhart. Playing as an individual, Brittany Smith struggled with a 93.
The Mustangs look for their second team win of the year when they play today's final round.
Oland, Smith lead MSU men into third
MUSCLE SHOALS, Ala. — The Midwestern State Mustangs got strong play from Derek Oland and Sam Smith to stand third after the first two rounds of the University of North Alabama Spring Classic at the Robert Trent Jones Golf Trail at the Shoals.
Oland and Smith are tied for fifth individually after finishing two rounds at 1-over 145s on the 7,126-yard course.
Oland fired a 4-under-68 in the morning, but followed with a 5-over-77 in the afternoon.
Smith, a junior from Archer City, opened up with a 1-under-71 and added a 2-over-74 in the afternoon.
Thanks to the pair, the Mustangs tallied a 297-298—595 to stand third. Host North Alabama leads at 573, with Wilmington standing in second at 587.
"Derek had great ball striking in the first round," MSU coach Jeff Ray said. "He eagled 17 and birdied 18 to come in at 68.
"Sam played well both rounds from tee to green. He struggled a bit on some of the greens."
The Mustangs got a 155 from Raine Copeland after rounds of 79 and 76, with Brett Perry adding a pair of 79s for a 158. Jeremy LeGuen posted a 156 for the day, as he started with an 85 in the first 18 and countered with a 1-under-71 in the afternoon.
The Mustangs conclude the tournament with today's final round.
Women's basketball
Mustangs to host annual tryouts
Midwestern State women's basketball will host its annual tryout on April 18 from 3-5 p.m. at D.L. Ligon Coliseum.
Prospects must fill out a tryout form and bring a recent physical examination from within the last six months to participate in workouts.
All current MSU students intending to tryout must email their name and MSU identification number to assistant coach Christopher Reay at firstname.lastname@example.com.
For more information, contact Reay at 397-4406.
Subscribe to the Times Record News
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You can now invite anyone to meet at your favorite Starbucks.
Limited-time feature
30 year old woman | Baton Rouge, LA, USA | Seeking men 27-34 within 75 miles
Lou'siana cook seeks good man.
I am currently working on my coursework for a PhD in American history at LSU. I would not be doing all of this except that I really want to teach in the university atmosphere. Of course, the job market is terrible for history PhDs, so I am open to working in public history, doing something with the family farm for a living, or some combination of the two. Of course, I may also just give up on academia and become a survivalist : ) If I have learned anything from my experience of attending 4 undergrad universities in 4.5 years (earning my BA from UNC-Chapel Hill in 2007), then going to pastry school, then back to the east coast for the MA, then back home to Louisiana, it's that making definitive plans for the future is often futile (also, living in a place for few months is a great way to experience travel). I do, though, know that I want to settle back near home eventually because it is where everything important is. My home and family mean the world to me. I am proud of my Louisiana heritage and my Dad's insistence on raising my sister's and me as part-time farm hands. I can do a lot of things many people don't know how to because of it (operate heavy equipment and repair fences, for example) and it has given me an invaluable sense of self-sufficiency. I am very close to my family and consider that a real blessing. As for what I am looking for: I want a real man, a guy that can stand on his own two feet, has a good relationship with his family, is educated, intelligent, fun, and does not take himself too seriously. I want someone who inspires and invigorates me, particularly when it comes to little travel adventures and physical activity. A guy that can or is willing to learn country/cajun dancing, is into the outdoors and enjoys getting dirty, but who can clean up well (to take me out dancing, of course) would be ideal. Confidence is attractive, obnoxiousness (especially about money) is not. 'Smiling eyes' are a bonus. As for politics, I am a fiscal conservative and social liberal; basically, libertarian. I would like to find someone with similar values. As I'm sure you know, it's difficult to really describe oneself particularly well, so if you'd like to know more, just ask! : )
Camping , Coffee and conversation , Business networking , Cooking , Dining out , Gardening/Landscaping , Hobbies and crafts , Movies/Videos , Music and concerts , Exploring new areas , Nightclubs/Dancing , Playing sports , Travel/Sightseeing , Volunteering , Wine tasting
Aerobics, Billiards / Pool, Cycling, Dancing, Inline skating, Martial arts, Other types of exercise, Swimming, VolleyBall, Weights / Machines, Yoga
I exercise 3-4 times per week.
I like Dogs, Horses
I desperately want a dog, but will not get one until I know I can give it enough room and attention, which can be difficult while working and in graduate school. My heart is set on a Great Dane or a Catahoula.
Some other viewpoint
Take me anywhere with mountains and/or pretty water to play in and I'll be happy. I like restaurants with a modern but friendly atmosphere and well-considered, well-executed dishes and a good bar to read at.
The University of North Carolina at Chapel Hill, Chapel Hill, NC
My favorite day is one where I get dirty at the farm then go out that evening in stilettos. I love thunderstorms, lightning at night, great dining experiences and cuddling (i know). Seeing a fun musician in a small venue with room to dance is great.
Eating out, cooking, baking and feed people. Domestic projects, like sewing and putting together furniture are fun. I have an increasing interest in garden-type projects at my dad's farm. I also like to target practice to blow off steam : )
That changes constantly with grad school because I have to read usually 3 books a week. As for fiction that I read in the evening to chill out, I have been in a Neil Gaiman mood and found a new interest in short stories.
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|What she is looking for
|5'8" (172cms)
|5'9" (175cms) to 8'0" (243cms)
|Body type:
|Slender, About average, Athletic and toned, A few extra pounds, Stocky
|Black, Blue, Brown, Grey, Green, Hazel
|Dark brown
|Black, Light brown, Dark brown, Blonde, Salt and pepper, Dark blonde, Bald
|No Way
|No Way
|Social Drinker
|Never, Social Drinker
|No preference
For my graduate assistantship, I work part time at the main library at LSU. I occasionally supplement my income by baking and one day want to be a tree farmer and hydroponic gardener : )
|I'll tell you later
|$25,001 to $35,000, $35,001 to $50,000, $50,001 to $75,000, $75,001 to $100,000, $100,001 to $150,000, $150,001+
|Never Married
|Never Married, Widow / Widower, Divorced
|Have kids:
|Yes, and they sometimes live at home, No, Yes, and they live away from home, Yes, and they live at home
|Wants kids:
|Definitely, Someday
|White / Caucasian
|Asian, Latino / Hispanic, Native American, Pacific Islander, White / Caucasian
I am a quarter Cajun, a quarter Sicilian, and the rest is a mix of western Europe.
|Christian / Catholic
|Christian / Catholic, Christian / Protestant, Christian / Other
|English, Spanish
|Graduate degree
|Bachelors degree, Graduate degree, PhD / Post Doctoral
I am ok with a guy that does not yet have his bachelor's if he has been in the military or something, but if that is the case, I highly prefer that he be actively working on earning his degree.