Wednesday, July 31, 2019

Literature-based discovery of diabetes

Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS. Methods We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 54 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets.Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature- derived targets in the pathogenesis of diabetic neuropathy. Results SciMiner identified 1,026 ROS- and diabet es-related targets from the 54 biomedical papers (http://Jdrf. eurology. med. umich. edu/ROSDiabetes/ webcite). Fifty-three targets were significantly over-represented in the ROS-diabetes literature ompared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice.For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG. Conclusions Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the athogenesis of diabetic neuropathy. Diabetes is a metabolic disease in which the body does not produce or properly respond to insulin, a hormone required to convert ca rbohydrates into energy for daily life. According to the American Diabetes Association, 23. million children and adults, approximately 7. 8% of the population in the United States, have diabetes [1]. The cost of diabetes in 2007 was estimated to be $174 billion [1]. The micro- and macro-vascular complications of diabetes are the most common causes of renal tailure, blindness and amputations leading to significant morta y, morbidity poor quality of life; however, incomplete understanding of the causes of diabetic complications hinders the development of mechanism-based therapies.In vivo and in vitro experiments implicate a number of enzymatic and non-enzymatic metabolic pathways in the initiation and progression of diabetic complications [2] including: (1) increased polyol pathway activity leading to sorbitol and fructose accumulation, NAD(P)-redox imbalances and changes in signal transduction; (2) non- enzymatic glycation of proteins yielding â€Å"advanced glycation end-productsâ €  (AGES); (3) ctivation of protein kinase C (PKC), initiating a cascade of intracellular stress responses; and (4) increased hexosamine pathway flux [2,3].Only recently has a link among these pathways been established that provides a unified mechanism of tissue damage. Each of these pathways directly and indirectly leads to overproduction of reactive oxygen species (ROS) [23]. ROS are highly reactive ions or small molecules including oxygen ions, free radicals and peroxides, formed as natural byproducts of cellular energy metabolism. ROS are implicated in multiple cellular pathways such as mitogen-activated protein kinase MAPK) signaling, c-Jun amino-terminal kinase ONK), cell proliferation and apoptosis [4-6].Due to the highly reactive properties of ROS, excessive ROS may cause significant damage to proteins, DNA, RNA and lipids. All cells express enzymes capable of neutralizing ROS. In addition to the maintenance of antioxidant systems such as glutathione and thioredoxins, pri mary sensory neurons express two main detoxifying enzymes: superoxide dismutase (SOD) [7] and catalase [8]. SOD converts superoxide (02-) to H202, which is reduced to H20 by glutathione and catalase [8].SODI is the main form of SOD in the cytoplasm; SOD2 is located within the itochondria. In neurons, SODI activity represents approximately 90% of total SOD activity and SOD2 approximately 10% [9]. Under diabetic conditions, this protective mechanism is overwhelmed due to the substantial increase in ROS, leading to cellular damage and dysfunction [10]. The idea that increased ROS and oxidative stress contribute to the pathogenesis of diabetic complications has led scientists to investigate different oxidative stress pathways [7,11].Inhibition of ROS or maintenance of euglycemia restores metabolic and vascular imbalances and blocks both the initiation and progression of omplications [1 2,13]. Despite the significant implications and extensive research into the role of ROS in diabetes, n o comprehensive database regarding ROS-related genes or proteins is currently available. In the present study, a comprehensive list of ROS- and diabetes-related targets (genes/proteins) was compiled from the biomedical literature through text mining technology.SciMiner, a web-based literature mining tool [14], was used to retrieve and process documents and identify targets from the text. SciMiner provides a convenient web-based platform for target-identification within the biomedical iterature, similar to other tools including EBIMed [1 5], ALI BABA [16], and Polysearch [1 7]; however, SciMiner is unique in that it searches tull text documents, suppo free-text PubMed query style, and allows the comparison of target lists from multiple queries.The ROS-diabetes targets collected by SciMiner were further tested against randomly selected non-ROS-diabetes literature to identify targets that are significantly over- represented in the ROS-diabetes literature. Functional enrichment analyses were performed on these targets to identify significantly over-represented biological unctions in terms of Gene Ontology (GO) terms and pathways. In order to confirm the biological relevance of the over-represented ROS-diabetes targets, the gene expression levels of nine selected targets were measured in dorsal root ganglia (DRG) from mice with and without diabetes.DRG contain primary sensory neurons that relay information from the periphery to the central nervous system (CNS) Unlike the CNS, DRG are not protected by a blood-nerve barrier, and are consequently vulnerable to metabolic and toxic injury [19]. We hypothesize that differential expression of identified targets in DRG would confirm heir involvement in the pathogenesis of diabetic neuropathy. Defining ROS-diabetes literature To retrieve the list of biomedical literature associated with ROS and diabetes, PubMed was queried using (â€Å"Reactive Oxygen Species†[MeSH] AND â€Å"Diabetes Mellitus†[MeSH]).This que ry yielded 54 articles as of April 27, 2009. SciMiner, a web-based literature mining tool [14], was used to retrieve and process the abstracts and available full text documents to identify targets (full text documents were available for approximately 40% of the 1 , 1 54 articles). SciMiner-identified targets, eported in the form of HGNC [HUGO (Human Genome Organization) Gene Nomenclature Committee] genes, were confirmed by manual review of the text. Comparison with human curated data (NCBI Gene2PubMed) The NCBI Gene database provides links between Gene and PubMed.The links are the result of (1) manual curation within the NCBI via literature analysis as part of generating a Gene record, (2) integration of information from other public databases, and (3) GeneRlF (Gene Reference Into Function) in which human experts provide a brief summary of gene functions and make the connections between citation PubMed) and Gene databases. For the 54 ROS-diabetes articles, gene-paper associations we re retrieved from the NCBI Gene database. Non-human genes were mapped to homologous human genes through the NCBI HomoloGene database.The retrieved genes were compared against the SciMiner derived targets. Any genes missed by SciMiner were added to the ROS-diabetes target set. Protein-protein interactions among ROS-diabetes targets To indirectly examine the association of literature derived targets (by SciMiner and NCBI Gene2PubMed) with ROS and diabetes, protein-protein interactions (PPIs) mong the targets were surveyed This was based on an assumption that targets are more likely to have PPIs with each other if they are truly associated within the same biological functions/pathways.A PPI network of the ROS-diabetes targets was generated using the Michigan Molecular Interactions (MIMI, http://mimi. ncibi. org/ webcite) database [20] and compared against 100 PPI networks of randomly drawn sets (the same number of the ROS-diabetes target set) from HUGO. A standard Z-test and one sample T-test were used to calculate the statistical significance of the ROS- diabetes PPI network with respect to the random PPI networks.Functional enrichment analysis Literature derived ROS-diabetes targets (by SciMiner and NCBI Gene2PubMed) were subject to functional enrichment analyses to identify significantly over-represented biological functions in terms of Gene Ontology [21], pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG, http://www. genome. ]p/kegg/ webcite) [22] and Reactome http://www. reactome. org/ webcite[23]). Fisher's exact test [24] was used to calculate the statistical significance of these biological functions with BenJamini-Hochberg (BH) adjusted p-value ; 0. 5 [25] as the cut-off. Over-represented ROS-diabetes targets Defining background corpora To identify a subset of targets that are highly over-represented within the ROS- diabetes targets, the frequency of each target (defined as the number of documents in which the target was identified divided by the n umber of total documents in the query) was compared against the frequencies in randomly selected background corpora.Depending on how the background set is defined, over-represented targets may vary widely; therefore, to maintain the background corpora close to the ROS and diabetes context, documents were selected from the same Journal, volume, and issue f the 54 ROS-diabetes documents, but were NOT indexed with â€Å"Reactive Oxygen Species†[MeSH] nor â€Å"Diabetes Mellitus†[MeSH]. For example, one of the ROS-diabetes articles (PMID: 18227068), was published in the Journal of Biological Chemistry, Volume 283, Issue 16. This issue contained 85 papers, 78 of which were not indexed with either â€Å"Reactive Oxygen Species†[MeSH] or â€Å"Diabetes Mellitus†[MeSH] indexed.One of these 78 papers was randomly selected as a background document. Three sets of 54 documents were selected using this approach and processed using SciMiner. Identified targets were con firmed by manual review for accuracy. Identifying significantly over-represented targets ROS-diabetes targets were tested for over-representation against targets identified from the three background sets. Fisher's exact test was used to determine if the frequency of each target in the ROS-diabetes target set was significantly different from that of the background sets. Any targets with a BH adjusted p-value < 0. 5 in at least two of the three comparisons were deemed to be an over-represented ROS- diabetes target. Functional enrichment analyses were performed on these over- represented ROS-diabetes targets as described above. Selecting targets tor real-time R A subset of targets were selected for RT-PCR from the top 10 over-represented ROS- diabetes targets excluding insulin and NADPH oxidase 5 (NOX5), which does not have a mouse ortholog. Nitric oxide synthase 1 (NOSI), the main generator of nitric oxide, ranked at the 1 5th position and was additionally selected for inclusion in th e test set.Differential gene expression by real-time RT-PCR Mice DBA/2J mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Mice were housed in a pathogen-free environment and cared for following the University of Michigan Committee on the Care and Use of Animals guidelines. Mice were fed AIN76A chow (Research Diets, New Brunswick, NJ). Male mice were used for this study. Induction of diabetes Two treatment groups were defined: control (n = 4) and diabetic (n = 4). Diabetes was induced at 13 weeks of age by low-dose streptozotocin (STZ) injections, 50 mg/kg/day for five consecutive days.All diabetic mice received LinBit sustained release insulin implants (LinShin, Toronto, Canada) at 8 weeks post-STZ treatment. Insulin implants were replaced every 4 weeks, at 12 and 16 weeks post-STZ treatment. At 20 weeks post-STZ treatment, mice were euthanized by sodium pentobarbital overdose and DRG were harvested as previously described [26]. Real-time RT-PCR The gene expression o f the selected nine literature-derived ROS-diabetes targets in DRG was measured using real-time RT-PCR in duplicate.The amount of mRNA isolated from each DRG was normalized to an endogenous reference [Tbp: TATA box binding protein; A cycle threshold (CT)]. Identification of ROS-diabetes targets A total of 1,021 unique targets were identified by SciMiner from the 1,154 ROS- diabetes papers defined by the query of (â€Å"Reactive Oxygen Species†[MeSH] AND â€Å"Diabetes Mellitus†[MeSH]) and confirmed by manual review. Table 1 contains the op 10 most frequently mentioned targets in the ROS-diabetes papers. Insulin was the most frequently mentioned target, followed by superoxide dismutase 1 and catalase. Table 1 .Top 10 most frequent ROS-diabetes targets The NCBI Gene2PubMed database, containing expert-curated associations between the NCBI Gene and PubMed databases, revealed 90 unique genes associated with the 54 ROS-diabetes papers (Additional File 1). SciMiner identified 85 out of these 90 targets, indicating a 94% recall rate. Five targets missed by SciMiner were added to the initial ROS-diabetes target set to result in 1,026 unique targets (Additional File 2). Additional tile 1. The list ot 90 genes trom the NCBI Gene2PubMed database tor the ROS-Diabetes literature (1 , 1 54 papers).Format: XLS Size: 35KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Additional file 2. The list of 1,026 ROS-Diabetes targets. Format: XLS Size: 229KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data PPI network of the ROS-diabetes targets The PPI network among the ROS-diabetes targets was evaluated using MIMI interaction data. This was based on the assumption that targets commonly related to certain topic are more likely to have frequent interactions with each other.One hundred PPI networks were generated for comparison using the same number of genes (1,026) randomly selected from the complete HUGO gene set (2 5,254). The PPI network of the ROS-diabetes targets was significantly different from the randomly generated networks indicating their strong association with the topic â€Å"ROS and Diabetes†. Table 2 demonstrates that the mean number of targets with any PPI interaction in the randomly generated target sets was 528. 9 (approximately 52% of 1,026 targets), while the number of targets with any PPI interaction in the ROS- iabetes target was 983 (96%).The number of targets interacting with each other was also significantly different between the random networks (mean = 155. 4) and the ROS-diabetes network (mean = 879). Figure 1 illustrates the distributions of these measurements from the 100 random networks with the ROS-diabetes set depicted as a red vertical line. It is obvious that the PPI network of the ROS-diabetes targets is significantly different from the random networks. Table 2. Summary of 100 randomly generated PPI networks thumbnailFigure 1 . Histograms of randomly gene rated PPI networks.The histograms llustrate the distributions of 100 randomly generated networks, while the red line indicates the ROS-diabetes targets. The network of the ROS-diabetes targets is significantly different from the 100 randomly generated networks, indicating the overlap of ROS-diabetes targets with respect to the topic â€Å"Reactive Oxygen Species and Diabetes†. Functional enrichment analyses of the ROS-diabetes targets Functional enrichment analyses of the 1,026 ROS-diabetes targets were performed to identify over-represented biological functions of the ROS-diabetes targets.After BenJamini-Hochberg correction, a total of 189 molecular functions, 450 biological rocesses, 73 cellular components and 341 pathways were significantly enriched in the ROS-diabetes targets when compared against all the HUGO genes (see Additional Files 3, 4, 5 and 6 for the full lists). Table 3 lists the top 3 most over-represented GO terms and pathways ranked by p-values of Fisher's ex act test: e. g. , apoptosis, oxidoreductase activity and insulin signaling pathway. Additional file 3. The enriched Molecular Functions Gene Ontology Terms in the 1,026 ROS-Diabetes targets.Format: XLS Size: 91 KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Additional file 4. The nriched Biological Processes Gene Ontology Terms in the 1,026 ROS-Diabetes targets. Format: XLS Size: 95KB Download file This tile can be viewed wit Microsott Excel Vieweropen Data Additional tile enriched Cellular Components Gene Ontology Terms in the 1,026 ROS-Diabetes targets. Format: XLS Size: 61 KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Additional file 6. The enriched pathways in the 1,026 ROS-Diabetes targets.Format: XLS Size: 104KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Table 3. Enriched functions of 1,026 ROS-diabetes targets Identification of over-represented ROS-diabetes targets To identify th e ROS-diabetes targets highly over-represented in ROS-diabetes literature, three sets of background corpora of the same size (n = 1 , 1 54 documents) were generated using the same Journal, volume and issue approach. The overlap among the three background sets in terms of documents and identified targets are illustrated in Figure 2.Approximately 90% of the selected background documents were unique to the individual set, while 50% of the identified targets were identified in at least one of the three background document sets. The frequencies of the identified targets were compared among the background sets for significant differences. None of the targets had a BH adjusted p-value ; 0. 05, indicating no significant difference among the targets from the three different background sets (See Additional File 7). thumbnailFigure 2. Venn diagrams of document compositions and identified targets of the randomly generated background sets.Approximately 90% of the selected background documents we re unique to individual set (A), while 50% of the identified targets were identified in at least one of the three background document sets (B). Additional file 7. Comparisons of target frequencies among three background sets. Format: XLS Size: 22KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Comparisons of the ROS-diabetes targets against these background sets revealed 53 highly over- represented ROS-diabetes targets as listed in Table 4.These 53 targets were significant (p-value ; 0. 05) against all three background sets and significant following BenJamini-Hochberg multiple testing correction (BH adjusted p-value ; 0. 05) against at least two of the three background sets. SODI was the most over-represented in he ROS-diabetes targets. Table 4. 53 targets over-represented in ROS-diabetes literature Functional enrichment analyses of the over-represented ROS-diabetes targets Functional enrichment analyses of the 53 ROS-diabetes targets were performed to identify over- represented biological functions.Following BenJamini-Hochberg correction, a total of 65 molecular functions, 209 biological processes, 26 cellular components and 108 pathways were significantly over-represented when compared against all the HUGO genes (see Additional Files 8, 9, 10 and 11 for the full lists). Table 5 shows the top 3 ost significantly over-represented GO terms and pathways ranked by p-values of Fisher's exact test. GO terms related to oxidative stress such as â€Å"superoxide metabolic process†, â€Å"superoxide release†, â€Å"electron carrier activity† and â€Å"mitochondrion† were highly over-represented 53 ROS-diabetes targets Additional file 8.The enriched Molecular Functions Gene Ontology Terms in the Over- represented 53 ROS-Diabetes targets. Format: XLS Size: 46KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Additional file 9. The enriched Biological Processes Gene Ontology Terms in the Over-represented 53 ROS- Diabetes targets. Format: XLS Size: 95KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Additional file 10. The enriched Cellular Components Gene Ontology Terms in the Over-represented 53 ROS-Diabetes targets.Format: XLS Size: 66KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Additional file 1 1 . The enriched pathways in the Over-represented 53 ROS-Diabetes targets. Format: XLS Size: 75KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data Table 5. Enriched functions of the 53 over-represented targets in diabetes Gene expression change in iabetes Two groups of DBA/2J mice exhibited significantly different levels of glycosylated hemoglobin (%GHb). The mean ? ± SEM were 6. 2 ? ± 0. for the non-diabetic control group and for 14. 0 ? ± 0. 8 for the diabetic group (p-value < 0. 001), indicative of prolonged hyperglycemia in the diabetic group [26]. DRG were harvested from these animals for gene expression assays. Nine genes were selected from the top ranked ROS-diabetes targets: superoxide dismutase 1 (Sodl), catalase (Cat), xanthine dehydrogenase (Xdh), protein kinase C alpha (Prkca), neutrophil cytosolic factor 1 Ncfl), nitric oxide synthase 3 (Nos3), superoxide dismutase 2 (Sod2), cytochrome b-245 alpha (Cyba), and nitric oxide synthase 1 (Nosl).Eight genes exhibited differential expression between diabetic and non-diabetic mice (p-value < 0. 05) as shown in Figure 3. Cat, Sodl, Sod2, Prkca, and NOSI expression levels were decreased, while Ncfl , Xdh, and Cyba expression levels were increased in diabetes. thumbnailFigure 3. Gene expression levels of selected ROS-diabetes targets in DRG examined by real-time RT-PCR. Expression levels are relative to Tbp, an internal control (error bar = SEM) (*, p < 0. 05; **, p < 0. 01; ***, p < 0. 01). Eight (Cat, Sodl, Ncfl , Xdh, Sod2, Cyba, Prkca, and Nosl) out of the nine selected ROS-diabetes genes were sign ificantly regulated by diabetes. Discussion Reactive oxygen species (ROS) are products of normal energy metabolism and play important roles in many other biological processes such as the immune response and signaling cascades [4-6]. As mediators of cellular damage, ROS are implicated in pathogenesis of multiple diseases including diabetic complications [27-30].With the aid of literature mining technology, we collected 1 ,026 possible ROS-related targets from a set of biomedical literature indexed with both ROS and diabetes. Fifty-three targets were significantly over-represented in the ROS-diabetes papers when compared against three background sets. Depending on how the background set is defined, the over-represented targets may vary widely. An ideal background set would be the entire PubMed set; however, this is not possible due to limited access to tull texts and intense data processing.An alternative method wou d be to use only abstracts in PubMed, but this may not fully represen t the literature. Using only the abstracts, our target identification method resulted in 21 (39%) of the 53 key ROS- iabetes targets (Additional File 12), suggesting the benefit of rich information in full text documents. In the present study, background documents were randomly selected from the same Journal, volume, and issue of the 54 ROS-diabetes documents, which were not indexed with â€Å"Reactive Oxygen Species†[MeSH] nor â€Å"Diabetes Mellitus†[MeSH].This approach maintained the background corpora not far from the ROS and diabetes context. Additional file 12. The Key 53 ROS-Diabetes Targets Identifiable Using Only the Abstracts. Format: XLS Size: 23KB Download file This file can be viewed with: Microsoft Excel Vieweropen Data The gene expression evels of nine targets selected from the 53 over-represented ROS-diabetes targets were measured in diabetic and non-diabetic DRG. Our laboratory is particularly interested in deciphering the underlying mechanisms of diab etic neuropathy, a major complication of diabetes.Data published by our laboratory both in vitro and in vivo confirm the negative impact of oxidative stress in complication-prone neuron tissues like DRG In an effort to obtain diabetic neuropathy specific targets, SciMiner was employed to further analyze a subset of the ROS-diabetes papers (data not shown). Nerve growth factor (NGF) was identified as the most over- epresented target in this subset when compared to the full ROS-diabetes set; however, NGF did not have statistical significance (BH adjusted p-value = 0. 06). The relatively small numbers of papers and associated targets may have contributed to this non-significance.Therefore, the candidate targets for gene expression validation were selected from among the 53 over-represented ROS-diabetes targets derived from the full ROS-diabetes corpus. Among the tested genes, the expression levels of Cat, Sodl , Sod2, Prkca, and NOSI were decreased, while the expression levels of Ncfl , Xdh, and Cyba were increased nder diabetic conditions. Cat, Sodl , and Sod2 are responsible for protecting cells from oxidative stress by destroying superoxides and hydrogen peroxides [8-11]. Decreased expression of these genes may result in oxidative stress [32].Increased expression of Cyba and Ncfl , subunits of superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex [30], also supports enhanced oxidative stress. Xdh and its inter-convertible form, Xanthine oxidase (Xod), showed increased activity in various rat tissues under oxidative stress conditions ith diabetes [33], and also showed increased expression in diabetic DRG in the current study. Unlike the above concordant genes, protein kinase C and nitric oxide synthases did not exhibit predicted expression changes in diabetes.Protein kinase C activates NADPH oxidase, further promoting oxidative stress in the cell [34,35]. Decreased expression of Prkca in our diabetic DRG is not parallel with expression levels of other enzymes expected to increase oxidative stress. Between the two nitric oxide synthases tested in the present study, NOSI (neuronal) expression was significantly decreased (p-value < 0. 01) in diabetes, while Nos3 (endothelial) expression was not significant (p-value = 0. 06). The neuronal NOSI is expected to play a major role in producing nitric oxide, another type of highly reactive free radical.Thus, with some exceptions, the majority of the differentially expressed genes in DRG show parallel results to the known activities of these targets in diabetes, suggesting enhanced oxidative stress in the diabetic DRG. Assessment of antioxidant enzyme expression in diabetes has yielded a variety of results [36-40] depending upon the duration of diabetes, the tissue studied and other factors. In diabetic mice and rats, it is commonly reported that superoxide dismutases are down-regulated [37-40], where data regarding catalase are variable [36,40].PKC is activated i n diabetes, but most papers that examined mRNA demonstrated that its expression is largely unchanged [41]. Among the 53 over-represented ROS-diabetes targets, SODI was the most over- represented and was differentially expressed under diabetic and non-diabetic conditions. To the best of our knowledge, no published study has investigated the role of SODI in the onset and/or progression of diabetic neuropathy. Mutations of SODI have long been associated with the inherited form of amyotrophic lateral sclerosis (ALS) [42] and the theory of oxidative stress-based aging [43].Early reports indicate that knockout of the SODI gene does not affect nervous system development [44], although recovery following injury is slow and incomplete [45,46]. With respect to diabetes, SODI KO accelerates the development of diabetic nephropathy [47] and cataract formation [48]. Thus, examining the SODI KO mouse as a model of diabetic neuropathy would be a reasonable follow-up study. One limitation of the cur rent approach using literature mining technology is incorrect r missed identification of the mentioned targets within the literature.Based on a performance evaluation using a standard text set BioCreAtlvE (Critical Assessment of Information Extraction systems in Biology) version 2 [49], SciMiner achieved 87. 1% recall (percentage identification of targets in the given text), 71. 3% precision (percentage accuracy of identified target) and 75. 8% F-measure (harmonious average of recall and precision = (2 x recall x precision)/(recall + precision)) before manual revision [14]. In order to improve the accuracy of SciMiner's results, each target was anually reviewed and corrected by checking the sentences in which each target was identified.Approximately, 120 targets (†10% of the initially identified targets from the ROS-diabetes papers) were removed during the manual review process. The overall accuracy is expected to improve through the review process; however, the review process did not address targets missed by SciMiner, since we did not thoroughly review individual papers. Instead, 5 missed targets, whose associations with ROS-diabetes literature were available in the NCBI Gene2PubMed database, were added to the final ROS-diabetes target list (Additional File 2).

Tuesday, July 30, 2019

Reed Supermarkets: a New Wave of Competitors

Reed Supermarkets. Spring 2013Meredith Collins faces the problem of choosing the most appropriate marketing strategy for Reed Supermarkets to implement so that the company increases its market share in the Columbus, OH market from 14% in 2010 to a target of 16% in 2011. This goal should be accomplished in spite of the new competitive challenges posed by the rising prominence of dollar and limited selection stores in the food retailing industry.SWOT AnalysisInternal Strengths Reed’s quality image and exceptionally attentive customer service;Full range offerings;Attractive stores, long hours, and elegant service? case displays.Internal WeaknessesMany consumers perceive Reed’s prices are high;Capital expenditure policy freezing; 3. No consensus within management on what strategy to implement for market share growth.External OpportunitiesThe new consumer is more savvy, health and cost? conscious;Growth of private label merchandise; 3. Columbus’s economic environment is more favorable than state’s and nation’s economic environments;External Threats Dollar and Limited Selection Stores increasing market share / Aldi’s projected new stores;Economic downturn; . Significant dwindling of customer loyalty.Reed’s management is currently assessing the following alternatives to increase its market share in the Columbus market:Continue its ongoing â€Å"dollar special† campaign;Terminate the â€Å"dollar special† campaign and implement an everyday low pricing model;Convey the value created to consumers by reinforcing the range and quality of offerings;Increase low priced specials, expand private label brands, and introduce double couponing.In addition, I would also consider the following alternative: Make an offer to buy some of Galaxy’s troubling Columbus stores.In evaluating the aforementioned alternatives, Reed’s management will have to take into account that, in order to meet the targeted market s hare of 16% in 2011, they will have to increase their sales volume by $94 million, which represents a 14% increase compared to 2010 (see appendix). The present â€Å"dollar special† campaign was an attempt from Reed’s to change consumer’s perception that they have higher prices. Some Reed’s managers are confident that in another six months they will be able to change this perception while, at the same time, they reinforce customer loyalty.However, some executives believe also that the campaign detracted from Reed’s quality image as it seemed to be too close to the offering of dollar stores which could damage Reed’s image through association. The scope of this campaign (250 out of 50,000 items) does not seem sufficient to generate the additional sales required. Other executives suggest implementing an everyday low pricing model in order to tackle, in a more aggressive fashion, the high? priced image that Reed carries. This would likely requir e a complete switch of the company’s positioning from a high? nd store to a medium, more value? focused positioning. Reed’s image, as a quality and customer service oriented, could be extremely damaged by such a switch. Additionally, it would be expected that other discount stores would be reacting aggressively to this strategy. Another option is to reinforce Reed’s current positioning as a high? end store by emphasizing the range and quality of its offerings. Such strategy appeals to the more affluent households, which are more keen on premium private labels and organic produce.This customer segment has been the backbone of Reed’s growth in the past 20 years, and the company wants to be ready to satisfy its upscale tastes as the economy recovers. Operations Director Jane Wu offered yet another alternative: increase low? priced specials, expand private label brands, and introduce double couponing. The new consumer that emerged from the 2007? 2009 recessio n is more savvy and cost? conscious, which is demonstrated by the increasing share of wallet captured by dollar and limited selection stores.By acknowledging this new reality and resorting to the strategy suggested by Director Wu, the company can potentially attract new customers and appeal to both fill? in â€Å"trippers† and full grocery â€Å"runners†. This seems to be a sound strategy in order for the company to capture, in the short? term, the $94 million additional sales required to meet the target market share. It is unclear, however, if this strategy could hurt the quality image recognized to Reed’s supermarkets and as a result drive high? nd customers away. On the other hand, during difficult economic times, such as the downturn of 2008? 2011, consumers tend to opt for value. Finally, we should not discard the introduction of new stores as a strong alternative for increasing sales. The company has consistently expanded the chain in the past, with the ne w stores accomplishing similar results to existing ones. Reed’s management has made it clear that it does not wish to have capital expenditures in form of new stores in 2011.But, a struggling Galaxy chain in the Columbus market could represent an interesting opportunity for Reed to acquire some of its stores at a discounted price, and this way meeting the sales volume required for the 16% market share. Given the resistance from Reed’s management to resort to additional capital expenditure, my recommendation is that the company implements the alternative suggested by Director Wu, i. e. increase low? priced specials, expand private label brands, and introduce double couponing. For the

Monday, July 29, 2019

Performance And Specifications Of Power Pumps Engineering Essay

IntroductionBackground:The agencies of pumping is the most of import manner of fluid transportation for 1000s of old ages. Ancient Egyptians used water wheels with hoppers for the motion of vehicle marked with H2O for irrigation intent. In the 3rd century BC ; the Grecian scientist Stisebeos Alexandria invents the reciprocating pump to pump H2O. The about the same clip discovered the Grecian mathematician Archimedes the prison guard pump, called the composit of mandolins with a coiling traveling on inside the cylinder. Till that clip the there was no much development occurs until the late 17th century, where the Gallic adventurer Denis invent a pump with consecutive blades. Then the British adventurer John Oblad invents the centrifugal pump with curving blades in 1851. Thereafter, the first usage of compressors with axial-flow turbo jet engines where found in the mid-fortiess of the 20th century AD.Reciprocating PumpPositive supplanting pumps are that type of machines which is common for applications that require a really high Pressures and comparatively low flow. In this machine, the liquid flows into a contained infinite, such as a cylinder, speculator, or rotor. Then a traveling Piston forces the liquid out of the cylinder, increasing the force per unit area. The usage of positive supplanting pumps is common in applications that require high discharge force per unit area and comparatively low flow. The discharge force per unit area generated by a positive supplanting pump is – in theory – space. If the pump is dead headed, the force per unit area generated will increase until either a pump portion fails or the driver stalls from deficiency of power. The Reciprocating Pump – besides known as Power Pump- is one type from the Positive Displacement Pump. In his book, Pollak illustrates that the Reciprocating pump has a random-access memory, speculator, Piston or other cylindrical component working backwards and forwards within a cylinder or pump barrel ; this gesture is normally delivered from a grouch go arounding unvarying velocity, and linking rod. Automatic valve control the flow of liquid into the cylinder, and out once more. A Piston or a speculator moves back and Forth in an enclosed cylinder. A reciprocating pump besides has a power terminal and a liquid terminal. Most piston pumps are individual playing ; plunger pumps are dual moving. The diameter of the Piston, the length of the Piston shot and the speed of the Walter pistons determine the pump capacity. See figPower Pumps:As mentioned by Igor Karassik in his book that the power pump does non develop force per unit area ; it merely produces a flow of fluid. The downstream procedure or shrieking system produces a opposition to this flow, thereby bring forthing force per unit area in the piping system and dispatch part of the pump. The flow fluctuates at a rate proportional to the pump velocity and figure of cylinders. The amplitude of the fluctuations is a map of the figure of cylinders. Karassik added that greater the figure of cylinders, the lower the amplitude of the flow fluctuations at a specific revolutions per minute. It is ever possible for the power pump to bring forth different capacity as they are capable of operating over a broad scope of velocities. Each pump has maximum suction and discharge force per unit area limits that ; when combined with its maximal velocity, find the pump ‘s power evaluation. The pump can be applied to power conditions that are less than its maximal evaluation but at a little lessening in mechanical efficiencyOperating Principles:In his paper, Samuel explains the pump operation as follows ; the reciprocating pump uses a crankshaft-connecting rod mechanism. The crankshaft-connecting rod mechanism converts the rotary motion of the crankshaft to a reciprocating additive motion of Pistons. The Piston motion creates volume alterations. As a pit opens when a Piston retracts, the fluid is admitted through an recess cheque valve. When the Piston reverses, the recess look into valve stopping points, and the pit reduces when the Piston extends. The mercantile establishme nt look into valve clears and the fluid is forced out by the Piston. Despite that of the fluid being pumped, the discharge volume is fixed for each crankshaft revolution. Pressure is determined by the system flow opposition and pump building. The Speed decrease is so needed for diminishing high velocity from the driver to low pump shaft velocity.Applications for Power pumps are:†¢ Oil well clay pumps †¢ Reverse osmosis charge pumps †¢ Auxiliary boiler provender pumps †¢ Pipeline pumps †¢ Oil field H2O injection pumps †¢ Slurry pumps †¢ Process pumpsPerformance and specifications:In his paper, David Parker negotiations about the specification illustrating that the quality and measure of information on suction conditions will find the ultimate success or failure of any pump installing. The bulk of pump jobs, start at the suction. There must be a minimal sum of absolute force per unit area available to provide fluid to the pump suction. PD pumps by and large require less absolute force per unit area. Net Positive Inlet Pressure Required ( NPIPR ) , at the pump suction rim, is the evaluation of entire recess losingss within that pump at rated conditions. Unit of measurements are force per unit area footings ; PSI, Kg/cm2, Bar, KPa. These losingss include the unstable clash loss along the internal suction way, the alteration in lift from the suction rim to the enclosed volume, the unstable clash loss of come ining the enclosed volume, and the acceleration to the speed of the enclosed volume. For any given size, NPIPR will increase with increased viscousness or flow ( increased flow = increased velocity ) . Volumes of gas are normally specified comparative to standard temperature and force per unit area ( STP ) of 680F and atmospheric force per unit area ; 14.7 psia ; 200C, 1.034 Kg/cm2 absolute. By stipulating the standard volume of gas and stipulating the suction force per unit area and temperature, the volume of gas nowadays at the pump suction can be calculated. This capacity must be added to the liquid capacity in order to size the pump for the needed liquid flow rate. If suction force per unit area is below atmospheric force per unit area, even little sums of entrained gas will spread out in volume necessitating a larger pump. Capacity should be defined for the rated status. If there is an acceptable scope of capacities, the lower limit and maximal acceptable should be stated. This allows pump providers to offer standard merchandises without holding to modify for specific capacity dem ands.Efficiency:In the reciprocating pump, merely two efficiency losingss need to be considered ; volumetric and Mechanical. Volumetric efficiency loss is provoked by slippage through valves, ratio of liquid chamber volume at terminal of shot to plunger/piston supplanting volume, and liquid squeezability. Mechanical efficiency loss occurs while get the better ofing mechanical clash in bearing and velocity decrease. The overall efficiency of a reciprocating pump unit is by and large above 85 % throughout its full operating scope. However, in the reciprocating pump can run over 90 % because many pumps and decrease units operate at a mechanical efficiency of 98 per centum, and the volumetric efficiency can frequently be above 95 per centum.Viscosity:Viscosity of a fluid is the ratio of shear emphasis to the rate of shear strain. It is a step of its opposition to flux. High viscousness fluids, like gum elastic, adhesives, or molasses, are really immune to forces applied to travel them. Low viscousness fluids, like kerosine or H2O, have really small opposition to coerce. Viscosity is reduced as temperature is increased ; hot fluids flow more readily than cold fluids. Viscosity should ever be given at a specified temperature. Typical units for viscousness are centipoises, centistokes, and SSU. Positive Displacement pumps maintain high efficiencies throughout the viscousness scope. Entrained gasses ca n be handled in big measures by most Positive Displacement pump designs ; nevertheless care must be taken in stipulating measure of gas entrained and flow required. Positive Displacement pumps are used to keep the changeless flow rate as nozzle force per unit areas change due to choke offing and gnawing. Precise control of fuel add-on rates increases the operators control over burning conditions. This in bend leads to cut down air emanations, a really critical concern in a extremely regulated industry. The reciprocating pump provides a about changeless flow rate over a wider scope of force per unit area ; the centrifugal pump gives unvarying force per unit area over a scope of flow, so it drops dramatically as the flow rate additions. On a reciprocating pump, fluid viscousness has small consequence on the flow rate as the force per unit area increases. However, unstable viscousness has a large impact on the centrifugal pump ‘s force per unit area and flow rate. The efficiency besides drops well.Advantages:Efficiency is rather high even though there are alterations in the needed caput. It can be up to 85 % to 95 % or even more. Merely with high velocity it tends to diminish somewhat. Reciprocating pumps run at much lower operating velocities than centrifugal pumps and therefore is better suited for managing viscose fluid. For a given velocity the flow rate is changeless regardless of caput, the pump is limited merely by the power of the premier mover and the strength of the pump parts. The fluid flow from the reciprocating pump is well high. It is start automatically. No demand to make full the cylinders before get downing. Disadvantages: There are poorer in managing liquids incorporating solids that tend to eat valves and seats. Because of the pulsating flow and force per unit area bead throw the valves they require larger suction force per unit area at the subdivision rim to avoid cavitations. Due to mechanical quivers, the pulsating flow require a particular attending to subdivision and discharge piping design Hovering gesture of the nozzle creates perturbations that travel at velocity of sound from the pump cylinder shrieking system. These perturbations cause the force per unit area degree of the system to fluctuate with regard to clip. It is hard to pump syrupy liquid in the reciprocating pump The cost of bring forthing Piston pumps is high. This is due to the really accurate sizes of the cylinders and Pistons. Besides, the geartrain needed to change over the rotary motion of the thrust motor into a reciprocating action involves excess equipment and cost. Discharge flow problems: Care cost a batch considered with its handiness, because throbing flow and big figure of traveling parts, as the atoms can acquire into the little clearances and cause terrible wear. The Piston pump therefore, should non be used for slurries. The throbing features of the fluid fluxing into and out of power pumps are significantly affected by the figure of Pistons. Discharge flow pulsings are the most critical because of the high energy potency generated when the system opposition reacts with the flow to make force per unit area. Since the magnitude of the discharge pulsing is largely affected by the figure of cylinders, so we can get the better of the pulsing flow by increasing the figure of cylinders. Besides, we can cut down the discontinuity by utilizing an collector at the terminal of the nose which will provides a continues flow.

Historical Change- Describe the drive for African American Civil Essay

Historical Change- Describe the drive for African American Civil Rights 1863 1968 - Essay Example is period only served to set precedence to later activities that culminated in great achievement not only for the blacks in American but also for the many people with similar problems across the globe. In America, the civil right movement focused much in the south, a region that was inhabited by a large African American population. This region was characterized by a blatant racial inequality in economic opportunity, education and legal and political process (Smith, & Wynn, 2009, pg 12-14). In 1808 the U.S congress abolished slave trade following the passage of the constitution which banned slavery. This became the central divisive matter in the early republic. Such is the case that this law came into force at a time when the south was heavily dependent on cheap slave labor for their agriculture contrary to the north that was speedily embracing industrialization. The newly found division between the south and north aggravated political and cultural differences and resulted to great animosity. One such difference revolved around the issue of admitting new states. Here, the question was as to whether to admit them as free or slave oriented. The effect of this crisis came up in 1820 when Missouri requested for admission stating its intention to operate a slave state. The north came out strongly against Missouri admission fearing that the slave holding states would gain majority share in the senate. This was however resolved through a compromise that saw Missouri granted i ts request as a slave state but not without the admission of a free Maine( cut out of Massachusetts). This move ensured preservation of the balance of power between the two antagonistic parties but never resolved the raging controversies. Following the growing antislavery campaigns, especially from the north, the abolitionist movement alongside other charities undertook a move that saw them purchase slaves with the sole aim of sending back to Africa, this was in the early 1800s. For instance,

Sunday, July 28, 2019

An Exploration of Apple's Dominance of the Smartphones Assignment

An Exploration of Apple's Dominance of the Smartphones - Assignment Example In addition to this, the other research questions will be that how the other organisations in the Smartphone industry trying to compete with Apple in UK’s market and what Apple can do to maintain its competitive advantage in the UK’s market. Apple, Inc. is an US based multinational company which was founded in the year 1976. The Smartphone industry in UK has been booming because of the continued increase in demand of Smartphone by the people in UK. Along with Samsung and Nokia, Apple is found to be dominating the UK Smartphone market (The Telegraph, 2012). According to the report of Kantar Worldpanel ComTech, the market share of Apple’s Smartphone increased by around 10% from 21% to 31% during the period of 12 weeks that ended on November 2011 (Virki, 2011).It is mainly attributed towards the release of new model of Smartphone in UK by Apple, named iPhone 4S during October 2011. However it has been argued that Apple is ranked second to the Android platform develo ped by Google in terms of market share in the Smartphone industry of UK (Warman, 2011). ... Research Background The proposed topic in this research study and the analysis of the findings based on the research done on the topic would provide an in-depth knowledge about the Smartphone industry in UK at present and the consumer behaviour patterns related to Smartphone products in UK. Smartphone is only a new concept in the field of mobile technology and is different from other standard mobile phones available in the market. As a result of these facts, the existing literature in this field is limited and not much research studies have been conducted till now. Hence, this research study would add to the existing literature and pave way to further research that can be done in this field. Moreover, Apple is a dominant player in the UK’s market of Smartphone products and has had its market dominance for a significant amount of time till now. It is evident from its market share in the Smartphone industry of UK which was around 31% during November 2011 (Virki, 2011). However, lot of other mobile companies are also introducing their Smartphone products in the UK’s market. This can have an effect on Apple’s market share in UK. According to the recent reports published by Kantar Worldpanel ComTech, Apple has fallen behind Google in terms of market share in the UK Smartphone industry. Android operating system installed in the Google Smartphone is being preferred by the consumers in UK more than Apple Smartphone (Arthur, 2012a). However, Android is divided amongst various brands like Samsung, HTC, Motorola, etc. Hence Apple iPhones which is the single branded Smartphone is the most used brand by the consumers in UK. Moreover, with respect to customer satisfaction, Apple is found to have the highest level of customer

Saturday, July 27, 2019

In What Ways Do We Inherit Our Ideas and Beliefs From Our Family and S Essay

In What Ways Do We Inherit Our Ideas and Beliefs From Our Family and Society - Essay Example From the family, the child learns to trust and grow, and family care leads to the development of the behaviours and beliefs of the child. If the environment provided by the family is nurturing and positive, the child grows up to be a successful and happy person. He takes on risk to learn new things as he knows he has the support of the family, and even if he fails, his family is there to support him. The negative support from the family can lead to a completely opposite effect. The example of family beliefs and its negative effect can be clearly seen in the literal work of William Faulkner and his short story â€Å"A Rose for Emily†. The story revolves around a daughter who is so distraught from the death of her father that she keeps his dead body to herself for a couple of days. She is so dependent on her father and secluded from the society that she refuses to let go of his body. Her dependency on father had led to her isolation from society, lack of a maternal figure and has disturbed relationships around. Another example of family and its emphasis on the lives of an individual is highlighted in the literal work of Shirley Jackson â€Å"The Lottery†, which shows how families can turn against one another on basis of a single trigger. Initially, it was highlighted in the story that family bonds were so strong that all families stood together and each family member has to be present. All the actions within the story are carried out due to the effect of family relationships. However, as soon as one of the members Tessie draws out a marked paper, all those family members turn against her and stone her. Another important factor that shapes the ideas and beliefs of an individual is the society, specifically the community. The sociological conditions have been affecting the individuals since the very beginning, however, each generation develops a new set of conditions. The present generation, for example, is socially ruled by the influence of technology, economy and media.  Ã‚  

Friday, July 26, 2019

Denialism Essay Example | Topics and Well Written Essays - 1250 words

Denialism - Essay Example In most cases of such dissenters, the stronger the emotion behind their beliefs, the more they are likely to invariably use cognitive inaccuracies to hold onto the false belief. In general, human beings tend to believe that there is a reason, and a physical logical one at that, why certain things happen. This especially true where emotional subjects such as the health of children is concerned. For example, they will feel that there is a reason why autistic children are that way. Some parents will also use examples of coincidental situations that occur to prove that there is a connection between autism and vaccinations. For instance, if a child dies soon after being vaccinated, its parents are likely to use that incident as justification for refusing to let their other children get vaccinated. Also, people have the tendency of expressing reservations on only the procedures that they are able to remember easily. In most cases where children receive vaccinations, they have no adverse re actions to them. This is an extremely common occurrence that is never reported on. Moreover, the media will report extensively whenever a child has adverse reactions to a vaccine. ... In the false consensus effect, parents are led to believe that the subject belief concerning the danger of vaccines is one which is widely held. This is mainly the result of being exposed to selective data through various elements of the media (Specter, 2009). In addition, most parents have no way of getting feedback from others about questions regarding this premise due to the unspoken rules regarding social interaction. For instance, if a parent suspects that his son or daughter is autistic because of the administrations of multiple vaccines, this view is not likely to be corrected by others or by doctors because it is unlikely that the parent will express it out loud. In recent years, the people who believe that vaccines cause autism have been influenced by the consistency with which the media reports on the subject of vaccines in relation to autism. It is also a fact that the parents who feel that vaccines are the actual cause of their children’s autism are more speak abou t it more often than those who do not believe this. Another reason why people might be persuaded about the accuracy of this inaccuracy is that it is the one issue over which they feel that they have control. Healthcare, in most nations, is the responsibility of government ministries; which many people distrust. Most citizens in nations around the world do not have a choice about the vaccines that their children get because governments have determined that the child’s rights to health are more important than the parent’s feelings about the matter. In some nations, children are vaccinated before being allowed to attend school while in others, parents are obligated to deliver the child to clinics for vaccinations. Many parents are irritated by the fact

Thursday, July 25, 2019

Cruise industry in India Essay Example | Topics and Well Written Essays - 1000 words

Cruise industry in India - Essay Example the stars. SIMPLICITY: Planning a cruise is simple; you're on board, nearly all expenses are pre- paid so vacation becomes hassle-free. FAMILY : Ideal for family vacation. PAMPERING. Regardless of your budget, all cruise lines pamper their guests with first- class service around the clock. SATISFACTION : It's a fact that cruises have a higher percentage of satisfied customers than any other vacation experience The cruise industry is the most exciting and fastest growing segment of the travel industry throughout the world today. The cruise market is strong throughout the world and particularly in the USA and UK. Currently, the Caribbean holds almost 67% of the market share in the total global cruise industry whilst the Far East (Asian Region) holds only 2%. The cruise companies targeting Indian customers feel that the cruise market segment in India is now coming of age. Not yet into the number game in terms of passengers, cruise liners have demarcated their market segments and clientele. Realising the competition and the objective, these companies have set their targets towards capturing the vast potential.The Indian travel industry can be virtually described as a melting pot of possibilities. India with its vast beautiful coastline and long historical and cultural traditions, theatre and performing art can be developed as a popular tourist destination for cruise tourism. The emerging trends like the rise in the standard of living, Modern lifestyle, enhanced economic standards, competitive work culture and the revelation of internet based technology in tourism and travel has made the planning vacation easier. Indian information technology... Indian information technology prowess lead to more economic stability and young and highly paid generation are looking for some unique experience. Cruise as depicted above have every component which gives a wonderful experience in a isolated ambience with first class facilities. The base price for a cruise from a short haul has suddenly opened up this segment to a seemingly infinite market. Eying this potential, cruise liners globally have drawing special strategies for the Indian market. Cruise companies are offering designer packages for their target audience. The promotional and marketing strategies are meticulously designed to suit the Indian consumer. Although the cruise liners had made their entry in the Indian market a few years ago, the operators are optimistic about the growth. The growth would be possible only by creating awareness about the entire experience of cruising as they realize that as a product, cruising is fairly new to the Indian travelers. The level of awarenes s with regards to cruising as a vacation option has increased considerably over the last few years. Cruising was considered to be either for the retired and the elderly or the rich and famous. Now-a-days honeymooners, entrepreneurs, senior corporate executives, adventure traffic and families are all part of clientele.

Wednesday, July 24, 2019

Freedom from Fear and Want in the Context of International Human Essay

Freedom from Fear and Want in the Context of International Human Rights Law - Essay Example Center of discussion in this paper is freedom from fear and want that appear to be unattainable aspirations. It is perhaps unreasonable to expect to live a life free of fear and want, unless the individual shares the upper echelons of society. The connection between freedom from fear and want with human rights is based on concepts of human security and human welfare. Essentially freedom from fear is a manifestation of the trend toward aligning human security with fundamental human rights at international law. Likewise, freedom from want adds to existing international human rights by extending fundamental liberties to include welfare as an arm of fundamental human rights. On its face, the inclusion of human security and welfare as an arm of international human rights is certainly consistent with developments in modern times particularly with respect to international poverty and international conflicts and terrorism. However, making human security and welfare a fundamental human right poses some problems with respect to protecting welfare and security and safeguarding other fundamental freedoms which may necessarily be contravened in the interest of promoting freedom from want and security. It may be misleading to think of international human rights as an international Bill of Human Rights because in the absence of a centralized system of enforcement, the recognition and enforcement of an international Bill of Rights are only as good as the national state’s implementation and enforcement of those rights. ... nternational Covenant on Civil and Political Rights 1976 (CCPR) and the International Covenant on Economic, Social, and Cultural Rights 1976 (CESR) (Meron, 1986). The International Bill of Human Rights has been expanded via a number of subsequent declarations, covenants and protocols internationally and regionally (Smith, 2007). It may be misleading to think of international human rights as an international Bill of Human Rights because in the absence of a centralized system of enforcement, the recognition and enforcement of an international Bill of Rights are only as good as the national state’s implementation and enforcement of those rights. It is one thing for a national government to recognize an international Bill of Human Rights and quite another for a national government to implement and enforce an international Bill of Human Rights. Even more uncertain is the economic ability of a national government to guarantee that citizens within its territories are accorded freedom from fear and want as legitimate arms of the international Bill of Human Rights. Be that as it may, it has been argued that the idea of international human rights was initially articulated by US President Franklin Delano Roosevelt in his â€Å"Four Freedoms† address to Congress on December 10, 1948. During that address, Roosevelt stated that his political aspirations were built around pursuing a social and political environment in which the â€Å"world† would be secure enough to safeguard four specific freedoms: the freedom of expression, religion, from want and fear (Power & Allison, 200, p. 4). Freedom of religion and freedom of expression are more easily achieved as the cost of enforcing free expression and free religion is arguably quite low compared to the cost of ensuring freedom from fear