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A Rarity: All 4 Leads Of Broadway's 'If/Then' Will Be On Stage In DenverWhen a Broadway show goes on the road the audience may get to see one of the Broadway leads on stage. But it is almost unheard of for all four of the leads to launch a national tour -- but that's what's happening with "If/Then" at the Buell Theatre.
Fall Theater Preview In DenverThis fall, many renowned shows will be stopping in Denver. Here is a quick preview of some top theater performances coming to the Mile High City.
'Matilda' Mom & Dad Actors Play Evil Characters, But It's 'A Lot Of Fun'The man and woman who plan Mrs. & Mr. Wormwood in "Matilda the Musical" which is now playing at Denver's Buell Theatre aren't bad people, but they enjoy playing bad people onstage.
Meet The 3 Young Ladies Who Play Matilda In 'Matilda The Musical'In a show called "Matilda the Musical" -- about a magical little girl -- they need many young actresses with high energy to pull off the part. Critic at Large Greg Moody met three young performers on their way to Denver to star in the show.
Why 'Wicked' Continues To Delight Year After YearIt's back by popular demand-- Wicked is showing at the Buell Theatre through July 5, in its fifth return to Denver.
It's A Plum Role For Actress Playing Diana Ross In 'Motown: The Musical'Diana Ross is an icon of both Motown and American music, so playing her on stage might seem to be an overwhelming challenge. But as Critic at Large Greg Moody found out, that's not the case for one actress.
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Hepatotoxicity is a form of liver injury caused by exposure to stressors. Genomic-based approaches have been used to detect changes in transcription in response to hepatotoxicants. However, there are no straightforward ways of using co-expressed genes anchored to a phenotype or constrained by the experimental design for discerning mechanisms of a biological response.
Through the analysis of a gene expression dataset containing 318 liver samples from rats exposed to hepatotoxicants and leveraging alanine aminotransferase (ALT), a serum enzyme indicative of liver injury as the phenotypic marker, we identified biological processes and molecular pathways that may be associated with mechanisms of hepatotoxicity. Our analysis used an approach called Coherent Co-expression Biclustering (cc-Biclustering) for clustering a subset of genes through a coherent (consistency) measure within each group of samples representing a subset of experimental conditions. Supervised biclustering identified 87 genes co-expressed and correlated with ALT in all the samples exposed to the chemicals. None of the over-represented pathways related to liver injury. However, biclusters with subsets of samples exposed to one of the 7 hepatotoxicants, but not to a non-toxic isomer, contained co-expressed genes that represented pathways related to a stress response. Unsupervised biclustering of the data resulted in 1) four to five times more genes within the bicluster containing all the samples exposed to the chemicals, 2) biclusters with co-expression of genes that discerned 1,4 dichlorobenzene (a non-toxic isomer at low and mid doses) from the other chemicals, pathways and biological processes that underlie liver injury and 3) a bicluster with genes up-regulated in an early response to toxic exposure.
We obtained clusters of co-expressed genes that over-represented biological processes and molecular pathways related to hepatotoxicity in the rat. The mechanisms involved in the response of the liver to the exposure to 1,4-dichlorobenzene suggest non-genotoxicity whereas the exposure to the hepatotoxicants could be DNA damaging leading to overall genomic instability and activation of cell cycle check point signaling. In addition, key pathways and biological processes representative of an inflammatory response, energy production and apoptosis were impacted by the hepatotoxicant exposures that manifested liver injury in the rat.
The liver is considered one of the vital organs in the body. Its has several major functions including the production of bile to break down fat, glycogen storage, decomposition of red blood cells, production of cholesterol, plasma protein synthesis and drug metabolism just to name a few. The latter takes place by a host of specialized detoxification enzymes and pathways that biochemically modify or metabolize xenobiotics to harmless metabolites and other byproducts for clearance from the body [1]. However, the metabolism of some drugs and compounds leads to toxic intermediates that can harm the liver and severely disrupt its function [2]. Drug-induced liver injury (DILI) is the leading cause of liver failure in the United States (US) and is quickly becoming a major concern world-wide [3]. In fact, DILI accounts for more than 50 percent of the cases of acute liver failure in the US and more than 75 percent of cases of adverse drug reactions result in liver transplantation or death [4]. Drug-induced hepatotoxicity is the most frequent cause for a drug to be withdrawn from the market, restricted in its use or have a warning associated with it due to adverse drug reactions [5]. A better understanding of the pathophysiology of DILI and the mechanisms involved in the manifestation of hepatotoxicity are critical to improving human health and public awareness of potentially harmful toxicants [6].
Microarray gene expression analysis has been used to study the effects of toxicants and other environmental stressors on biological systems [7-11]. Recently, Lobenhofer et al. [12] used gene expression data from rats exposed to a compendium of hepatotoxicants to show that blood gene expression patterns could be used not only to classify animals based on the compound they were exposed to, but also to provide a reasonable indication of the severity level of liver injury. In addition, Bushel et al. [13] demonstrated that gene expression profiles from rat blood samples could accurately predict exposure levels of acetaminophen to the rat liver better than traditional clinical panels. Furthermore, human subjects treated with acetaminophen could be classified based on blood gene expression levels. Although these efforts led to informative conclusions about the genes expression changes related to drug-induced hepatotoxicity, they did not capture the breath of the biological mechanisms altered by the toxic insult.
While hierarchical clustering groups genes and samples by the similarity of expression across all the elements in a data matrix, biclustering [14-17] aims to identify sub-matrices (subsets of rows [genes] and subsets of columns [samples] from an original data matrix) of gene expression that are coherent and possess homogeneity of co-expression. Hence, the biclusters contain co-expressed genes that represent distinct biological responses related to mechanistic changes. In this paper we used a biclustering method to analyze a compendium gene expression dataset containing 318 liver samples from rats exposed to hepatotoxicants (in a dose response and time series manner) and leveraged alanine aminotransferase (ALT), a serum enzyme indicative of liver injury, as the phenotypic marker in order to identify biclusters of co-expressed genes that over-represent biological processes and pathways related to hepatotoxicity.
Experimental design
Male 12 week old F344 Fischer rats were exposed to one of the following chemicals: 1,2-dichlorobenzene, 1,4-dichlorobenzene, bromobenzene, monocrotaline, N-nitrosomorpholine, thioacetamide, galactosamine or diquat dibromide [12]. For each chemical, four to six rats (two in one case), were exposed to three or four different dose levels (from subtoxic to toxic) of the compound and sacrificed at 6, 24 and 48 hrs later to extract liver RNA for microarray hybridization. The 318 samples and exposure conditions are listed in Table 1. The number of samples in each group varied from 32 to 72. Liver necrosis was observed in all the rats exposed to one of the eight chemicals at high doses (Table 2). However, 1,4-dichlorobenzene is an isomer of 1,2-dichlorobenzene and is non-toxic at low and mid doses. Since each compound has its unique chemical structure and properties, the activated biological processes, molecular pathways, extent of toxicity in the liver and injury could be highly similar or dissimilar. Considering these variables, we partitioned the columns of the gene expression data matrix into eight groups (one for each chemical) for analysis using Coherent Co-expression (cc)-Biclustering.
Table 1. The eight chemical compounds in the compendium
Table 2. Percent of necrosis of the hepatocytes
Identification of co-expressed genes based on ALT enzyme levels
Each group of chemicals included a set of samples with different exposure conditions (different doses and time points). We used ALT as a profile to supervise the extraction of the genes that are expressed similarly and correlated with the phenotypic marker. ALT values in each of the chemical exposures were generally elevated from 6, 24, to 48 hrs and from low doses to high doses. For a probability threshold (pt) value of 0.001, supervised cc-Biclustering extracted 84 biclusters in which the genes were correlated (r-value >= 0) to ALT and 76 biclusters in which the genes were anti-correlated (r-value < 0) to ALT. The number of genes in each bicluster varied. The largest number of genes in a bicluster was 713. The number of groups (chemicals) in the biclusters had a range from a minimum of 1 to a maximum of 8. The biclusters which contained only one chemical could represent the uniqueness in gene expression for the agent and the biclusters which contained all eight chemicals could provide some clues to the common responses to the exposures across the agents.
Figure 1 displays heat maps of two biclusters which included all eight groups of chemicals. There are 87 genes in Figure 1A (the top half) and 86 genes in Figure 1B (the bottom half) significantly correlated and anti-correlated to the ALT profile, respectively. From Gene Ontology analysis of the genes in the biclusters, it was revealed that the significantly over-represented KEGG pathways and biological processes that are up-regulated included general mechanisms such as translation and biosynthetic processes from the genes correlated with ALT and down-regulated categories such as response to external stimuli, negative regulation of coagulation and macromolecule metabolism/biosynthesis from the anti-correlated genes (Table 3). It is interesting that none of the over-represented categories appeared to be related to liver injury. Figure 2 shows heat maps of two biclusters which consisted of seven groups of chemicals not including 1,4-dichlorobenzene. There are 182 genes correlated to the ALT profile in Figure 2A (the top half) and 76 anti-correlated genes in Figure 2B (the bottom half). Gene Ontology analysis revealed that over-represented KEGG pathways and biological processes included a defense response, wound healing, cell proliferation and hematopoietic migration from the genes correlated with ALT and categories related to lipid and steroid metabolism as well as the alkylation of amino acids, tryptophan and sulfur metabolism from the anti-correlated genes (Table 4).
Table 3. Significant biological processes and pathways of a general response across all chemicals
Table 4. Significant biological processes and pathways from the hepatotoxicant exposures
Figure 1. Heat maps of two biclusters containing samples from all exposures and genes correlated with ALT. The red color indicates up-regulation and the green color down-regulation. (A) 87 genes up-regulated in the top half and (B) 86 genes down-regulated in the bottom half were significantly correlated and anti-correlated to the ALT profile respectively. From left to right are (1) 1,2-dichlorobenzene, (2) 1,4-dichlorobenzene, (3) bromobenzene, (4) diquat dibromide, (5) galactosamine, (6) monocrotaline, (7) N-nitrosomorpholine and (8) thioacetamide. Each chemical has its dose exposure from low (left) to high (right). Each chemical dose has its time duration from 6 (left), 24 (middle), to 48 hrs (right).
Figure 2. Heat maps of two biclusters from samples exposed to hepatotoxicants and genes correlated with ALT. (A) 182 genes up-regulated in the top half and (B) 76 genes down-regulated in the bottom half were significantly correlated and anti-correlated to the ALT profile respectively. From left to right are (1) 1,2-dichlorobenzene, (3) bromobenzene, (4) diquat dibromide, (5) galactosamine, (6) monocrotaline, (7) N-nitrosomorpholine and (8) thioacetamide. Note that 1,4-dichlorobenzene was excluded from these two biclusters. The doses and time points have the same order as in Figure 1.
The Gene Ontology analysis of three biclusters from two chemicals, galactosamine and thioacetamide, revealed interesting categorization of the genes (see Additional file 1 Figure S1 and Table S1). The 401 genes in a bicluster subset by galactosamine over-represented a KEGG pathway related to extracellular matrix (ECM) receptor interaction (Figure S1A). Another bicluster of 364 genes subset by thioacetamide had a different set of significantly over-represented categories representing the Wnt signalling pathway and glycerophospholipid metabolism (Figure S1B). The third bicluster of 289 genes subset by both chemicals had biological processes and KEGG pathways related to neuron development and cell adhesion as over-represented categories (Figure S1C).
Additional file 1. Supervised and unsupervised cc-Biclustering details, pseudo code and supplemental figures and table.
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Identification of co-expressed genes that discern isomers and an early response
Although the blood serum level of ALT is a good indicator of liver injury, it is not considered a prognosticator of toxic insult as the true nature and extent of the liver damage is not proportional to the elevation in the serum enzyme activity [18]. For instance, a normal ALT level does not necessarily mean that the liver is definitely normal and high levels of ALT in the blood doesn't necessarily indicate the extent to which the liver is inflamed or damaged. In addition, it is likely that ALT levels elevate well after the mechanistic changes have occurred that led to the liver injury from toxic exposure. Therefore, we set out to use cc-Biclustering in an unsupervised fashion (without ALT) so we could find biclusters of genes that may be unrelated to ALT or respond before ALT elevation and yet are very informative in terms of the manifestation of hepatotoxicity. We obtained more biclusters (~ three times more) using unsupervised cc-Biclustering when the same threshold pt was used as in the supervised case.
Similar to the biclusters in Figure 1, the genes in the heat maps shown in Figure 3 are subset by all eight chemicals. There are 330 genes up-regulated as shown in Figure 3A (the top half) and 409 down-regulated genes as shown in Figure 3B (the bottom half). Compared to the number of genes in the bicluster shown in Figure 1, the bicluster in Figure 3 contained about four to five times more genes and more significant categories (Table 5). The set of genes that are up-regulated were found to over-represent biological processes and KEGG pathways representative of a more toxic response (i.e. less similar to the general responses over-represented by the genes in the bicluster from the supervised clustering [Figure 1A]). Apoptosis, an inflammatory response and glycolysis/gluconeogenesis were key mechanisms impacted. The set of down-regulated genes contained over-represented categories related to cholesterol biosynthesis, fatty acid metabolism, alkaloid biosynthesis and the peroxisome proliferator-activated receptors (PPARs) signaling pathway. PPAR-α is mainly expressed in the liver and activation of the receptor has been associated with suppression of apoptosis and induction of cell proliferation [19].
Table 5. Significant biological processes and pathways of a more toxic response
Figure 3. Heat maps of two biclusters containing all samples and genes unconstrained by ALT. (A) 330 co-expressed genes are up-regulated in the top half; (B) 409 co-expressed genes are down-regulated in the bottom half. The samples are ordered the same as in Figure 1.
Heat maps of the gene expression from three biclusters subset by seven chemicals (excluding 1,4-dichlorobenzene), are shown in Figure 4. Figure 4A (the top) shows 175 co-expressed genes up-regulated at a later time and Figure 4B (the middle) 114 co-expressed genes down-regulated. The set of up-regulated genes significantly over-represented categories that are suggestive of liver regeneration (Table 6) [20,21]. Angiogenesis, the regulation of actin cytoskeleton, regulation of adherens (adhesion) junctions and the Toll-like receptor (TLR) signaling pathway were impacted. The down-regulated genes over-represented mechanisms related to energy producing pathways (glucose homeostasis, gluconeogenesis and the pentose phosphate pathways). Comparisons of the over-represented categories between the genes in Figure 3 and 4 clearly differentiate 1,4-dichlorobenzene from the other chemicals since the biclusters in Figure 4 do not contain genes that are co-expressed in the samples exposed to 1,4-dichlorobenzene. Figure 4C (the bottom) had 47 genes up-regulated early and significantly over-represented categories pointing to a negative regulation of protein kinase activity, the mitogen-activated protein kinase (MAPK) signaling pathway, and apoptosis (Table 6).
Table 6. Significant biological processes and pathways discerning isomers and from an early toxic response
Figure 4. Heat maps of three biclusters containing genes discerning isomers or depicting an early response to the toxic exposure. (A) 175 co-expressed genes are up-regulated (top); (B) 114 co-expressed genes are down-regulated (middle). (C) 47 co-expressed were up-regulated (bottom). The samples are ordered the same as in Figure 2.
Discussion and Conclusion
Over the recent years several ways of investigating drug-induced hepatotoxicity has been explored. Using gene expression analysis of samples exposed to toxicants offers a genome-wide assessment of the transcriptional changes that occur from the insult. However, current methodologies for analyzing the data are limited in that they typically do not "anchor" the changes in gene expression to the phenotype of toxicity nor do they constrain them by the experimental design. Case in point is hierarchical clustering of genes and samples based on gene expression data. Although the method provides an overall view of the clusters of genes that are co-expressed within a group of highly similar samples, it does not extract subclusters of co-expressed genes that are related to a given phenotype, end-point measure of the samples or subset of experiments. Yoon et al. [17] proposed a method for discovering coherent biclusters from gene expression data using decision diagrams constituted from binary representations of a set of samples in which the expression of a subset of genes are highly similar (coherent). However, the method does not integrate phenotypic data nor is it guided by the experimental design (i.e. constraints imposed by a time series or dose response study). Linking co-expressed genes to a phenotype of interest or set of experimental conditions can potentially enhance the interpretation of the biological systems that are impacted from the manifestation of an outcome [22].
We analyzed a compendium gene expression dataset containing 318 liver samples from rats exposed to hepatotoxicants and leveraged alanine aminotransferase (ALT), a serum enzyme indicative of liver injury as the phenotypic marker, to identify several biological processes and molecular pathways that may be associated with mechanisms of hepatotoxicity. Our analysis used an approach to biclustering called Coherent Co-expression Biclustering (cc-Biclustering) for clustering of a subset of genes through a coherent (consistency) measure within each group of samples representing a subset of experimental conditions. Existing biclustering methods use some measure of merit to determine whether a row (gene) or column (sample) should be included or excluded from a bicluster [23]. cc-Biclustering uses a given coherent measure (CM) to determine whether a gene or a group of samples is included or excluded from a bicluster. The CM used between pairs of gene vectors (or gene vectors with a phenotypic profile) is flexible. Depending on a research interest, CM can be chosen to be Pearson correlation, Euclidean distance or some other measure of (dis)similarity. Unsupervised cc-Biclustering uses a pairwise comparison of the gene expression profiles to extract biclusters. In the case of supervised cc-Biclustering, we correlated the co-expression of the subset of genes within a bicluster with ALT. The overlap between the up-regulated genes from the supervised and unsupervised cc-Biclustering methods is 61 genes (Additional file 1; Figure S2) where as the overlap between the down-regulated genes from the two methods is 78 genes (Additional file 1: Figure S3). The sharp contrast between biclusters in Figure 1 and Figure 2 with respect to the over-represented biological categories exhibited by the genes positively correlated with ALT clearly differentiated 1,4-dichlorobenzene from the other seven chemicals. This finding is consistent with a study to predict the levels of necrosis in the rat liver using this same compendium of hepatotoxicants [24]. It was shown that 1,4-dichlorobenzene was the only chemical with an observed necrosis contained in less than 25% of the hepatocytes (one sample was < 25%, 4 samples were < 5%, and 31 samples had no sign of necrosis). All the other chemicals caused observed necrosis in > 50% of the hepatocytes in one or more of the exposed samples (Table 2). Moreover, a bicluster with samples exposed to bromobenzene, diquat dibromide, galactosamine, monocrotaline or N-nitrosomorpholine and 12 genes (including Cd40, Casp8 and Nr4a1) correlated with ALT and contained over-represented categories related to an inflammatory response, glycolysis/gluconeogenesis and apoptosis (Data not shown). These are biological processes known to be involved in hepatotoxicity [24,25].
Comparison of the over-represented categories between the genes in the biclusters shown in Figures 3 and 4 (both from the unsupervised biclustering) also differentiate 1,4-dichlorobenzene from the other chemicals quite well. In addition, 47 genes in a bicluster were found to be up-regulated early in response to the hepatotoxicant exposure (Figure 4C bottom) and significantly over-represented categories related to negative regulation of protein kinase activity, the MAPK signaling pathway, and apoptosis (Table 6). Many genes in this set (Atf4, Trib3, Jun, Btg2, Gadd45a, Gadd45b, Ddit3, Cdkn1a, Hmox1, Cdk9, Bag5 and Mcl1) have been extensively studied in terms of their response to toxicants or other external stimuli [26-31]. Most of these genes are targets of p53 and cause DNA damage. Our finding suggests that the liver injury caused by 1,4-dichlorobenzene could be non-genotoxic while the other toxicants could be genotoxic. This result is consistent with the current finding that early responses of some genes at 6 hr differentiate 1,4-dichlorobenzene from the other seven more toxic chemicals where it is evident that transcriptional regulation by Jun and TP53 leads to necrosis [24].
Although the data from each array is independently collected, in a vast number of cases, many of the related biological samples are highly correlated. For example, some samples are from the same tissue, or treated by the same chemical, or a time series. Same samples are merely biological replicates. In our study we analyzed rat liver samples exposed to one of eight chemicals. Each of the hepatotoxicants has its unique chemical structure and causes different levels and extent of liver injury (Table 2). The activated biological processes and molecular pathways can be highly similar or dissimilar. The gene sets involved in responding to each of the hepatotoxicants can overlap to a large extent or be somewhat unique. Using our biclustering approach we were able to capitalize on the experimental design and/or phenotypic measure to discern possible mechanisms of hepatotoxicity through the over-representation of pathways and biological processes determined by co-expressed genes in cc-Biclusters. More work is underway to efficiently process the wealth of biclusters extracted for a more informed interpretation of the mechanistic changes that take place during the formation of hepatotoxicity.
Gene expression data
Male 12 week old F344 Fischer rats were individually exposed to one of the following chemicals: 1,2-dichlorobenzene, 1,4-dichlorobenzene, bromobenzene, monocrotaline, N-nitrosomorpholine, thioacetamide, galactosamine or diquat dibromide. All eight chemicals were studied using standardized procedures, i.e. a common array platform, experimental procedures and data retrieving and analysis processes. For details of the experimental design see Lobenhofer et al[12]. Briefly, for each chemical, four to six male rats were exposed to a low dose, mid dose(s) or a high dose of the chemical and sacrificed at 6, 24 or 48 hrs later. At necropsy, the liver of the rats were harvested for RNA extraction. A time-matched vehicle control pool was made for each chemical by pooling equal amounts of RNA from each of the control animals. Each treated animal was hybridized against a time-matched control pool to the Agilent Rat Oligonucleotide Microarray with a dye-swap technical replicate. Fluorescence intensities were measured with an Agilent DNA Microarray Scanner and processed with the Agilent Feature Extraction software version A.7.5.1 for bromobenzene and 1,2-dichlorobenzene arrays and version 220.127.116.11 for the others. See the header of the Agilent data files for more details of the scanning and data acquisition hardware and software parameters. The 318 samples and exposure conditions are listed in Table 1. Liver necrosis was observed in all the rats exposed to one of the eight chemicals at high doses. However, 1,4-dichlorobenzene is an isomer of 1,2-dichlorobenzene and is non-toxic at low and mid doses. Since each compound has its unique chemical structure and properties, the activated biological processes, molecular pathways, type of toxicity in the liver and injury could be highly similar or dissimilar. Considering these variables, we partitioned the columns of the gene expression data matrix (Additional file 2) into eight groups (one for each chemical) for analysis using cc-Biclustering (Additional file 3). The number of samples in each group varied from 32 to 72. The data is publicly available at the Gene Expression Omnibus (GEO) database http://www.ncbi.nlm.nih.gov/geo/ webcite under series GSE15785 and at the Chemical Effects in Biological Systems (CEBS) database http://cebs.niehs.nih.gov webcite under accession number 001-00001-0020-000-4.
Additional file 2. Two-dimensional matrix of the gene expression ratio data (data preprocessed and fluor-flips per biological sample merged [averaged]).
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Additional file 3. Sample information denoting biological replicates for cc-Biclustering.
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Clinical chemistry
At sacrifice, blood was collected into serum separation tubes (BD Microtainer® Tubes, BD, Franklin Lakes, NJ) and serum was separated. Clinical chemistry analyses of alanine aminotransferase (ALT) was performed on all rats at study termination. Serum levels of the established liver injury marker ALT (Additional file 4) increase when the liver shows inflammation, injury or hepatotoxicity.
Additional file 4. ALT data for the biological samples.
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Rather than obtaining coherent measures across the whole vector of gene expression, cc-Biclustering uses the sample information in the study design of the experiment to partition the M columns into J groups according to a given phenotypic response or biological study of interest. For instance, as shown in the next section where an expression matrix has eight different chemicals, each group corresponds to a chemical with which samples (biological replicates included) are treated at different doses and time points. A gene expression value of an element in matrix A now has four indices, i.e.
where row index i is from 1 to N number of genes; the column index breaks up into three sub-indices, j, k, and l. The index j is from 1 to J number of groups (i.e., each of the groups corresponds to a chemical). The index k is from 1 to K number of treatments within a group (i.e., corresponding to a given chemical, a treatment is exposure to a given dose at a given time point). The index l is from 1 to L, where L is the number of biological replicates. The general idea of cc-Biclustering is to map matrix A to a binary coherent matrix H(hi, j) according to an inclusion\exclusion criterion function. The H matrix has N rows and J columns.
The advantages of bracketing samples or conditions into a set of groups are four-fold. (1) A coherent measure of expression is computed within a group to determine if a gene aij is included in a bicluster, where aij is a vector of expression values of ith row and jth group. (2) Gene expression aij can be time and/or dose series derived. If there were several replicates at a given time and dose, aij is evaluated to determine if it is differentially expressed and should be included in a bicluster. (3) The coherent measure (CM) used between pairs of gene vectors ai1,j and ai2,j (or phenotypic profile Sj) is flexible. Depending on a research interest, CM can be chosen to be Pearson correlation, Euclidean distance, or some other measure of biologically relevant similarity. (4) The cc-Biclustering algorithm is simple. Like many coherent value based models (such as an additive model, multiplicative model or based on a given CM) cc-Biclustering converts a gene expression matrix A to a binary matrix H with a given p-value threshold. The extracted biclusters then have constant rows and columns [15]. We used the DAVID database (April 2008 version) for Gene Ontology (January 2008 download) biological processes and KEGG pathway (January 2008 download) analyses of the genes within the biclusters and used p-values for over-representation of these biological categories based on a one-tailed Fisher exact probability or EASE score [32]. The supervised and unsupervised cc-Biclustering algorithms are described in more detail and depicted in pseudo code (Additional file 1). A comparison of the analysis of a microarray gene expression data set from Arabidopsis thaliana samples treated with various conditions and times of exposure using unsupervised cc-Biclustering and the Cheng and Church biclustering algorithm [33] with parameters δ = 0.5, α = 1.2 and output = 10 biclusters revealed that our method produced the top 3 biclusters of genes (by size) which are highly correlated within the subset of samples that shared similar exposure conditions with a Pearson correlation in the range of +0.73 to +0.84 whereas the other method produced the top 3 biclusters of genes with correlation in the range of +0.01 to +0.55.
Authors' contributions
JWC and PRB designed the strategy of cc-Biclustering. JWC implemented the cc-Biclustering algorithm, analyzed the data and wrote part of the manuscript. PRB provided suggestions, advice and guidance for the concept of the research, interpreted the results and also wrote part of the manuscript. The authors have read and approved the final manuscript.
We thank the National Center for Toxicogenomics at the National Institute of Environmental Health Sciences (NIEHS) for the hepatotoxicant compendium data. We also thank Jennifer Fostel and David Fargo for their critical review of the manuscript. This research was supported, in part by, the Intramural Research Program of the NIH and NIEHS.
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text: Tonight we have our first listing that's also viewable in virtual reality, as the Democratic Party's presidential debate airs on CNN and via NextVR's streaming (click here for instructions on viewing via Gear VR headset, and it's also on CNN.com but in 2D). Bigger news still, is the release of Netflix's first original movie, Cary Fukunaga's Beasts of No Nation with Idris Elba. Sci-fi fans will want to check out the final episode of Continuum (finally airing here in the US), and on Saturday night Tracy Morgan will be back on SNL. Gamers (that aren't still powering through tracks on the new Rock Band) can check out the first episode of Telltale Games' Minecraft: Story Mode on any system or Yoshi's Woolly World on Wii U, while Aladdin and Team America: World Police top the Blu-ray drops this week. Look after the break to check out each day's highlights, including trailers and let us know what you think (or what we missed).


text:
Calories in Pummelo (Pomelo)
Wondering how many calories are in Pummelo (Pomelo)?
Pummelo (Pomelo)
Chinese Grapefruit
B+ Grade
72 Calories
Nutrition Facts
Serving Size 1 cup, sections (190 g)
Per Serving % Daily Value*
Calories 72
Calories from Fat 1
Total Fat 0.1g 0%
Saturated Fat 0g 0%
Polyunsaturated Fat 0g
Monounsaturated Fat 0g
Cholesterol 0mg 0%
Sodium 2mg 0%
Potassium 410.4mg 12%
Carbohydrates 18.3g 6%
Dietary Fiber 1.9g 8%
Sugars 0g
Protein 1.4g
Vitamin A 0% · Vitamin C 193%
Calcium 1% · Iron 1%
*Based on a 2000 calorie diet
Pummelo (Pomelo) Calories and Health Benefits
- No saturated fat
- No cholesterol
- Very low in sodium
- No sugar
- High in dietary fiber
- High in potassium
- Very high in vitamin C
Get Nutritional Facts and the Health Benefits for Pummelo (Pomelo)
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Jenny found Calorie Count when she decided to stop dieting and start living better. She started logging her food, and was shocked by how many calories she was actually consuming. By making smarter choices, and being kinder to herself, she was able to reach her weight loss goal. Now, at 60 lbs. lost, and 4 months maintaining her weight, she is more confident and living a healthier and happier life.
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text:
Editions Larousse and Le Cordon Bleu have once again pooled their knowledge and are delighted to announce the launch of the new 'Petit Larousse Chocolat' Collector's edition on September 22, 2015. This new book, which is dedicated to chocolate in all its shapes and forms, contains 170 illustrated recipes and includes 11 new illustrated recipes, 23 new photos and 1 chapter entirely dedicated to 17 techniques in chocolate decoration.
Make your dream come true and experience a complete and intensive training in Paris, the capital of gastronomy, to discover the secrets of Cuisine and Pastry.
Become a leader in the restaurant business on an international scale. This program gives students all the skills necessary to develop their business and make it a success.
For gourmet enthusiasts and those who want to be initiated into the world of gastronomy, a wide range of courses in various disciplines are offered at the school.
Le Cordon Bleu will be in London, Turkey and Middle East in October 2015. Meet us to ask any questions you may have on our schools and programs.
This month, beets are in the spotlight at Le Cordon Bleu Paris, with this 100% vegetarian recipe. The Chefs offer you a delicate dish where the sweet notes of cooked beet balance perfectly with the tartness of Granny Smith apple.
The 6th edition of the International Culinary Photography Festival takes place from 1 May to October 31 2015. The patron is the three star Michelin Chef Yannick Alléno, elected best Chef of the year by Gault & Millau. This year, the theme is "Feeding the planet, energy for life" in order to highlight the Universal Exposition in Milano 2015.
The graduation ceremony of Le Cordon Bleu Paris students took place on September 18, 2015. The ceremony was held at the 'Cercle de l'Union Interalliée' with graduate's family members and friends. On this special day, Le Cordon Bleu was honored to welcome Thomas Goval as class patron.
The final episode of the 2nd edition of MasterChef Brasil took place in September. Izabel Alvares is the lucky winner of this successful TV show in Brazil.
Gaston Acurio awarded by UNESCO
A ceremony in honor oF Gaston Acurio was organized at UNESCO in appreciation of his determination to make Peruvian gastronomy achieve worldwide recognition.
Choosing Paris, the sentimental capital of gastronomy, is a guarantee that you will receive culinary training from the greatest French Chefs with international experience. They will teach you to master techniques for producing regional and national Cuisine.
The unparalleled blend of tradition and dynamic modernity is what makes Paris so beautiful. Paris, the City of Light and capital of romance, has a unique historical heritage and an abundance of cultural sites, monuments and museums to be visited.
You can also discover the bistros, Michelin-starred restaurants and even stroll along the famous avenues nibbling a croissant or baguette. Take in the department stores or simply wander around the winding streets while shopping for fashion, home ware, luxury, high-tech goods and of course epicurean treats.
Le Cordon Bleu looks forward to welcoming you to experience the highlights of gastronomic know-how and Parisian cultural life.


text:
Book your room at Best Western Golf & Hotel Du Gouverneur
Get an overview of this hotelFamily-friendly hotel with 2 restaurants and outdoor pool
Located in Monthieux, this family-friendly hotel is 0.2 mi (0.3 km) from Golf du Gouverneur, and within 6 mi (10 km) of Parc des Oiseaux and Golf du Clou. Espace Baignade Les Cascades and Musee de Cires are also within 9 mi (15 km).
Hotel Features
2 restaurants, an outdoor pool, and a fitness center are available at this hotel. Free WiFi in public areas and free self parking are also provided. Other amenities include a bar/lounge, a business center, and conference rooms.
Room Amenities
All 53 rooms offer free WiFi, minibars, and flat-screen TVs with satellite channels. Guests will also find room service, free local calls, and free bottled water.Information missing or incorrect? Tell us!
Hotel Amenities
Hotel Amenities
Best Western Golf & Hotel Du Gouverneur features an outdoor pool and a fitness center. Dining is available at one of the hotel's 2 restaurants. A bar/lounge is on site where guests can unwind with a drink. High-speed wireless Internet access is complimentary.
This 3-star property offers access to a business center. This family-friendly hotel also offers a terrace, multilingual staff, and laundry facilities. Onsite self parking is complimentary.
- 24-hour front desk
- Bar/lounge
- Breakfast available (surcharge)
- Business center
- Conference space
- Elevator/lift
- Express check-out
- Fitness facilities
- Free self parking
- Free WiFi
- Laundry facilities
- Luggage storage
- Multilingual staff
- Number of buildings/towers - 2
- Number of floors - 2
- Number of restaurants - 2
- Outdoor pool
- Safe-deposit box at front desk
- Tennis on site
- Terrace
- Total number of rooms - 53
Family Friendly Amenities
- Cribs/infant beds (complimentary)
- Free Wi-Fi
- Laundry facilities
- Outdoor pool
- Rollaway/extra beds available
Available in all rooms: Free WiFi
Available in some public areas: Free WiFi
Free self parking
Room Amenities
- Access via exterior corridors
- Air conditioning
- Climate control
- Free bottled water
- Free cribs/infant beds
- Desk
- Flat-panel TV
- Free local calls
- Free WiFi
- Hair dryer
- Iron/ironing board (on request)
- Minibar
- Phone
- Private bathroom
- Rollaway/extra beds available
- Room service (limited hours)
- Satellite TV service
Where to Eat
Club House - This restaurant specializes in French cuisine and serves lunch only.
La Table d Antigny - This restaurant specializes in French cuisine and serves dinner only.
Room service (during limited hours) is available.
Nearby Things to Do
Recreational amenities at the hotel include an outdoor pool and a fitness center.
The recreational activities listed below are available either on site or nearby; fees may apply.
- Golfing nearby
- Bicycle rentals nearby
- Hiking/biking trails nearby
To make requests for specific accessibility needs, complete the "Special or Accessibility Requests" section of "Trip Preferences" when you book your hotel.
- Accessible path of travel
- Accessible bathroom
- Roll-in shower
- Accessible parking
- In-room accessibility
Hotel Policies
Check-in time starts at 3 PM
Check-out time is noon
Payment types
Children and extra beds
- Children are welcome.
- Rollaway/extra beds are available for EUR 15 per night.
- Free cribs (infant beds)!
Pets allowed
You need to know
Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
- A city/local tax will be charged
- Resort fee: EUR 1.10 per person, per night
Optional extras
- Breakfast fee: EUR 13 per person (approximately)
- Pet fee: EUR 10 per pet, per night
- Rollaway bed fee: EUR 15 per night
National Rating
This hotel has received its official star rating from the French Tourism Development Agency, ATOUT France.


text:
Flavored Dental Floss
Shop Our New and Best Flavored Dental Floss
(2 Reviews)
As if dental floss wasn�t enough we also have our unique flavored toothpaste! Available in bacon, pickle and cupcake flavors, these unique toothpastes make great gag gifts and party favors! Keep your chompers clean without losing the delicious food tastes in your mouth by purchasing all of our unique flavor floss and toothpastes we have in stock! You'll love it and your dentist will love it!


text:
netconstructor (Christian Hochfilzer)
NetConstructor is a San Diego based company founded by Christian Hochfilzer, Leo Baghdassarian and Kris Fredrickson and is composed of a tightly-knit group of talented and experienced professionals in the realm of (UX) design, web, mobile, and large scale application developments / ETL integration. At the heart of NetConstructor is the simple belief that results speak for themselves. We understand that regardless of how aesthetically pleasing an advertisement or website may be, or how much theoretical sense the technique makes, unless the campaign produces the desired results, it has failed.
At NetConstructor, we pride ourselves in utilizing technology to develop innovative ROI-focused solutions that help our clients embrace the constantly evolving business place. We measure success by results. As such, we maintain an acute focus on how what we're doing will have an impact where it counts: your bottom line.
Recente documentactiviteitAlle activiteit weergeven
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text:
2 youths killed as train hits them in Dinajpur
Two youths are killed as a train hit them in Hakimpur upazila of Dinajpur.
Dinajpur headmaster suspended for beating 3 female students
A high school headmaster is suspended following a public outrage over three female students of Class VIII being beaten mercilessly in Birganj upazila of Dinajpur.
Indian nurse cuts off 8-day-old child's finger
Hospital nurse cuts off a finger of newborn child in a government hospital of Dinajpur in West Bengal of India.
2 killed as BGB opens fire on smugglers
At least 2 locals are killed and 3 others injured as Border Guard Bangladesh members opened fire after being attacked by smugglers in Dinajpur.
3 die in Dinajpur road crash
Three passengers were killed as a bus hit a banyan tree in Ghoraghat upazila of Dinajpur.
Teesta: Sand in winter, flood in monsoon (video)
Ahead of Indian Prime Minister Narendra Modi's Bangladesh visit, people living by the Teesta River are hopeful that the Teesta water sharing agreement will be signed during his visit.
3 madrasa teachers held for torturing student
Police picks up three madrasa teachers in Dinajpur Sadar Upazila for their alleged involvement in torturing a student accused of stealing.
BSF kills Bangladeshi in Dinajpur border
Indian Border Security force (BSF) shoots down a Bangladeshi at Birail upazila of Dinajpur.
Lychee farmers worried despite expected bumper harvest (video)
Lychee farmers and traders in Dinajpur expect a bumper harvest of lychee this year. However, they are worried about incurring loss due to the present political unrest in the country.
Teen killed in Dinajpur bomb blast
A teenage boy is killed as a crude bomb went off in Nawabganj upazila of Dinajpur


text:
How the NFL Put a Fork in Defense
If there's one category of athlete that doesn't need any more lucky breaks from the world, it's the NFL quarterback.
Here's a group whose members make tens of millions in salary, hoard Super Bowl MVP awards, dabble in the celebrity dating circuit and earn more endorsing cars, televisions and fur-lined boots than the rest of their teammates combined.
Yet it's the quarterback, more than any other player, who has been the NFL's biggest winners lately. Passing is up nearly 60 yards per game since 2003. The leaguewide completion percentage has never been higher. This season's 44.4 points-per-game average was the highest since 1965 and two quarterbacks, Drew Brees of the New Orleans Saints and Tom Brady of the New England Patriots, topped the previous all-time single-season mark for passing yards.
On Thursday, the top two picks in the NFL draft will almost certainly be Stanford quarterback Andrew Luck and Baylor's Robert Griffin III. If Texas A&M's Ryan Tannehill is taken in the top five, as many believe he will be, this would rank as one of the most prolific quarterback drafts in history.
The story is a nice one for quarterbacks, and in many ways for the league, which seems to be thriving amid all this offense. NFL experts say the passer's ascent is partly due to the inevitable evolution of the game. But a number of NFL players and executives say the current state of affairs is largely the result of a movement the league has been engineering for nearly a decade: a war on defense.
On Jan. 18, 2004, the Indianapolis Colts took on the New England Patriots in an AFC Championship game that was, even by the most charitable description, a slow and ugly mess. Taking full advantage of the NFL's rules at the time, the Patriots jammed the Colts receivers at the line of scrimmage, impeding their ability to run their routes in a way that would allow Indianapolis quarterback Peyton Manning to involve them in his aerial magic. The Patriots intercepted Manning four times and went on to win, 24-14.
After the season, the NFL's competition committee, which is made up owners, coaches and executives, decided to have a chat about these rules. According to one league executive who was briefed on the matter, the game between the Colts and Patriots became a focal point. Using that game as an example, this person said, the committee concluded that the referees should be directed to crack down on defenders who try, as the Patriots had, to disrupt pass plays before they begin. The following season, the number of "illegal contact" penalties called on defenders shot up to 191 from just 79 the season before.
Troy Brown, who played both wide receiver and defensive back for the Patriots, said he noticed an immediate difference in the way games were officiated. "You saw the calls come after that," he said. "You couldn't put a finger on a guy or it's called 'impeding.' If your elbow came across the chest of a guy while you were in front of him it was called. If your hand happened to be on a jersey when a guy was making a turn, they were calling those things."
Brown said the change produced some awkward defenses in subsequent years: Since players couldn't be as physical with receivers at the line, teams would try all kinds of new tricks, like dropping linemen into pass coverage.
Former Colts general manager Bill Polian, whose team lost that ugly game to the Patriots, acknowledged that during the 2004 meeting, which he attended, the competition committee agreed that illegal contact needed to be called more often. He said it's a "wives tale" that one game led to the change. Polian noted that while the number of illegal contact penalties rose initially, it has since declined. Last season, there were 92.
NFL spokesman Brian McCarthy noted that while scoring is currently high by historical standards, it's actually down from other periods in NFL history. In 1965, he noted, NFL teams scored an average of one more point per game.
NFL experts say many factors have conspired to make quarterbacks more dominant. For one thing, they say, recent rules aimed at protecting passers and receivers from helmet-to-helmet hits have given offenses more confidence. The passers are also better trained; as high schools and colleges install wide-open "spread" passing offenses, quarterbacks are learning to play bigger roles. And the rise of summer football leagues that feature seven-on-seven play have allowed quarterbacks to work on their throwing year round. Tannehill said Wednesday that playing all year had been a "huge" part of his development.
Former Tampa Bay linebacker Derrick Brooks, who played from 1995 to 2008, said last year's NFL labor deal, which limited practices with pads and off-season training, has had a disproportionate impact on defenses—which need to hit people to be effective. Under the new system, teams basically ask players "to show up on game day and get it down," he said. "That's tough."
Tod Maher, president of a group called the Professional Football Researchers Association, said he believes the NFL has clearly tweaked the rules to "inflate pass completions." He said if the league continues to do this, games will start to look like the Pro Bowl, "and those games aren't very interesting."
Atlanta Falcons president Rich McKay, the current competition committee chair, said at the league's annual meeting last month that there was "some concern" over passing statistics. But he said that Joel Bussert, a football historian who works for the league, made a presentation that showed that the current era of offense resembled the 1950s, when the league had some of its best quarterbacks and saw an explosion in popularity. "We've kind of gone back and looked at it and said, 'We feel OK about where we are,'" McKay said.
Write to Kevin Clark at email@example.com


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South Dakota
Sponsored By
After Record Storms, FEMA Sends Temporary Houses To Pine Ridge ReservationThe federal government is sending temporary housing to South Dakota's Pine Ridge Indian Reservation, where residents are still recovering from severe storms last spring.
South Dakota Woman Accused Of Assault With A Selfie StickA Sioux Falls woman is accused of assaulting her boyfriend with a selfie stick.
Stolen Giant Pumpkin Returned To South Dakota GrowerA 100-pound pumpkin that was brazenly stolen from the yard of a South Dakota residence has been found and returned, after someone apparently tried but failed to turn it into a giant jack-o'-lantern.
Statewide 4-H Pop Tab Collection Helps Ronald McDonald HouseThe South Dakota State 4-H Youth Council has collected 1,250 pounds of pop can tabs to help the Ronald McDonald House provide families with a place to stay while their child is in the hospital.
Student Charged With Attempted Murder In S. Dakota ShootingA teenage student has been charged with attempted murder in the shooting of a South Dakota high school principal who was lightly wounded in the arm, authorities said Thursday.
S. Dakota High School Principal Shot, Wounded; Students SafeThe principal of a South Dakota high school has been wounded in a shooting at the school. School officials say a suspected shooter is in custody and students are reported safe.
South Dakota Native American Tribe To Open First Ever Marijuana ResortA small South Dakota Native American tribe is taking on a new venture to attract tourism. The Santee Sioux are opening the nation's first marijuana resort on its reservation.
South Dakota Man Convicted In Death Of Adrian Peterson's SonA South Dakota jury on Tuesday convicted a man of second-degree murder and other charges in the death of the 2-year-old son of Minnesota Vikings running back Adrian Peterson.
Trial Of Man Accused Of Killing Peterson's Son In 2nd WeekThe prosecution has rested its case in the South Dakota trial of a man accused of killing the 2-year-old son of Minnesota Vikings running back Adrian Peterson.
Survey Suggests Economy Slowing In Rural Parts Of MinnesotaA new survey suggests that the economy will slow down in rural parts of 10 Western and Plains states -- including Minnesota -- in the months ahead. Creighton University economist Ernie Goss says weak crop and energy prices are hurting profits across the region.
Minnesota Man Dies After Police Chase In South DakotaA Minnesota man was killed after authorities said he fled from a Highway Patrol trooper in South Dakota's Brookings County and crashed. Fifty-eight-year-old Douglas Bixby, of Windom, Minnesota, died late Sunday after crashing his car into a ditch embankment and a tree.
Man Accused Of Killing Adrian Peterson's Son To Stand TrialA man accused of killing the 2-year-old son of Minnesota Vikings running back Adrian Peterson two years ago is set to stand trial in South Dakota.


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Rosario Picardo tells the still unfolding story of Embrace Church, a United Methodist Community meeting in the historic Kentucky Theatre in the heart of downtown Lexington. This little book will encourage clergy and laity alike, especially those in the midst of the hard work of church planting or church revitalization. The resource would be ideal for church planting teams.
15,000 Water Balloons and 40 Other Games, Icebreakers, and Ideas is an ebook written by Youth Ministry Collective authors—men and women who are in the trenches of youth ministry day in and day out. The games in this ebook have withstood the test of teenagers. Trust us—no one wins when we share the...
24 + 6 Ways to Think, Talk, Write, and Preach about the Sabbath Based on the book 24/6: A Prescription for a Healthier, Happier Life (Tyndale, 2014) by Matthew Sleeth.
We are pleased to team up with Roger E. Olson to offer you this free ebook: Arminianism FAQ: Everything You Always Wanted to Know. Roger is a leading voice on the issues surrounding the biblical understanding of salvation and has spent the last few years of his life bringing clarity...


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Defense Acquisitions:
Rapid Acquisition of MRAP Vehicles
GAO-10-155T: Published: Oct 8, 2009. Publicly Released: Oct 8, 2009.
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As of July 2008, about 75 percent of casualties in combat operations in Iraq and Afghanistan were attributed to improvised explosive devices. To mitigate the threat from these weapons, the Department of Defense (DOD) initiated the Mine Resistant Ambush Protected (MRAP) program in February 2007, which used a tailored acquisition approach to rapidly acquire and field the vehicles. In May 2007, the Secretary of Defense affirmed MRAP as DOD's most important acquisition program. To date, about $22.7 billion has been appropriated for the procurement of more than 16,000 MRAP vehicles. This testimony today describes the MRAP acquisition process, the results to date, lessons learned from that acquisition, and potential implications for improving the standard acquisition process. It is mostly based on the work we have conducted over the past few years on the MRAP program. Most prominently, in 2008, we reported on the processes followed by DOD for the acquisition of MRAP vehicles and identified challenges remaining in the program. To describe DOD's approach for and progress in implementing its strategy for rapidly acquiring and fielding MRAP vehicles, we reviewed DOD's plans to buy, test, and field the vehicles and discussed the plans with cognizant department and contractor officials. To identify the remaining challenges for the program, we reviewed the results of testing and DOD's plans to upgrade and sustain the vehicles
DOD use of a tailored acquisition approach to rapidly acquire and field MRAP vehicles was successful. The program relied only on proven technologies and commercially available products; established minimal operational requirements; and undertook a concurrent approach to producing, testing, and fielding the vehicles. To expand limited production capacity, indefinite delivery, indefinite quantity contracts were awarded to nine commercial sources, with DOD agreeing to buy at least 4 vehicles from each. Subsequent orders were based on a concurrent testing approach with progressively more advanced vehicle test results and other assessments. To expedite fielding of the vehicles, the government retained the responsibility for final integration in them of mission equipment packages including radios and other equipment. DOD also made MRAP its highest priority acquisition, which helped contractors and others more rapidly respond to the need and meet production requirements, in part by early investing of their own capital to purchase steel and other critical components in advance of orders. Schedule and performance results for MRAP were very good overall. In July 2008, nearly all testing was completed; the Marine Corps had placed orders for 14,173 MRAPs; and, as of May 2008, 9,121 vehicles had been delivered. As of July 2009, 16,204 vehicles have been produced and 13,848 vehicles fielded in two theaters of operation. Total MRAP production funding was about $22.7 billion, mostly through supplemental appropriations. In terms of lessons learned, MRAP's success was driven by several factors, including quick action to declare its acquisition DOD's highest priority and giving it a DX rating, which allowed access to more critical materials than was otherwise available. The availability of supplemental appropriations was also essential. However, while neither of these factors are practically transferable to other programs, decisions to 1) use only proven technologies, 2) keep requirements to a minimum, 3) infuse significant competition into contracting, and 4) keep final integration responsibility with the government all led to positive outcomes and may be transferable. Challenges to MRAP remain in its reliability, mobility, and safety, which required some modifying of designs and postproduction fixes, and adapting how vehicles were used. Also, long term sustainment costs are not understood and the services are only now deciding how MRAP fits them in the longer term. GAO's multiple best practices reports have underscored the need for the use of mature technologies, well understood requirements, systems engineering knowledge, and incremental delivery of capabilities to enable quicker deliveries. Finally, a broader lesson learned is that it is time to invest the time, money, and management skills in the science and technology community to enable the effectiveness we expect from the acquisition community.
Oct 1, 2015
Ford Class Aircraft Carrier:Poor Outcomes Are the Predictable Consequences of the Prevalent Acquisition CultureGAO-16-84T: Published: Oct 1, 2015. Publicly Released: Oct 1, 2015.
Tricare Pharmacy Pilot:Improved Monitoring Needed with Expansion of Pilot RequirementsGAO-15-768: Published: Sep 30, 2015. Publicly Released: Oct 1, 2015.
Sep 28, 2015
DOD Financial Management:Continued Actions Needed to Address Congressional Committee Panel RecommendationsGAO-15-463: Published: Sep 28, 2015. Publicly Released: Sep 28, 2015.
Sep 21, 2015
- Department of Defense's Waiver of Competitive Prototyping Requirement for the Air Force's F-15 Eagle Passive/Active Warning and Survivability System (EPAWSS) ProgramGAO-15-800R: Published: Sep 21, 2015. Publicly Released: Sep 21, 2015.
Sep 17, 2015
Prepositioned Stocks:Marine Corps Needs to Improve Cost Estimate Reliability and Oversight of Inventory Systems for Equipment in NorwayGAO-15-651: Published: Sep 17, 2015. Publicly Released: Sep 17, 2015.
Sep 9, 2015
Defense Infrastructure:In-Kind Construction and Renovation Projects Initiated by DOD during Fiscal Year 2013GAO-15-649: Published: Sep 9, 2015. Publicly Released: Sep 9, 2015.
Military Compensation:DOD Needs More Complete and Consistent Data to Assess the Costs and Policies of Relocating PersonnelGAO-15-713: Published: Sep 9, 2015. Publicly Released: Sep 9, 2015.
Sep 3, 2015
Military Personnel:Additional Steps Are Needed to Strengthen DOD's Oversight of Ethics and Professionalism IssuesGAO-15-711: Published: Sep 3, 2015. Publicly Released: Sep 3, 2015.
Aug 27, 2015
Weapon System Acquisitions:Opportunities Exist to Improve the Department of Defense's Portfolio ManagementGAO-15-466: Published: Aug 27, 2015. Publicly Released: Aug 27, 2015.
Aug 26, 2015
Regionally Aligned Forces:DOD Could Enhance Army Brigades' Efforts in Africa by Improving Activity Coordination and Mission-Specific PreparationGAO-15-568: Published: Aug 26, 2015. Publicly Released: Aug 26, 2015.
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