Pathway Hunter Tool (PHT) � A Platform for Metabolic Network Analysis and Potential Drug Targeting

Metabolic network analysis will play a major role in �Systems Biology� in the future as they represent the backbone of molecular activity within the cell. Recent studies have taken a comparative approach toward interpreting these networks, contrasting networks of different species and molecular types, and under varying conditions. We have developed a robust algorithm to calculate shortest path in the metabolic network using metabolite chemical structure information. A divide and conquer technique using Maximal Common Subgraph (MCS) approach and binary fingerprint was used to map each substrate onto its corresponding product. Then for the calculation of the shortest paths (using modified Breadth First Search algorithm) the two biochemical criteria �local� and �global� structural similarity were used, where �local similarity� is defined as the similarity between two intermediate molecules and �global similarity� is defined as the amount of conserved structure found between the source metabolite and the destination metabolites after a series of reaction steps. The pathway alignment was introduced to find enzyme(s) preference in the pathway of various organisms (a local and global outlook to metabolic networks). This was also used to predict potentially missing enzymes in the pathway. A novel concept called �load points� and �choke points� identifies hot spots in the network. This was used to find important enzymes in the pathogens metabolic network for potential drug targets

Recycling of Steel Scraps as a Strength Enhancement Material in Concrete

The cement industry is very energy consumptive and produces CO2 and also generates greenhouse gases which are the major cause of global warming. The production of cement and the use of concrete are both rising daily. So, to protect the environment, alternate materials are required. The construction industry has several constructional byproducts and wastes as a variant of traditionally used products. In the process of production and working with steel, steel chips are formed as waste material. The best way to reduce environmental pollution and improve waste recycling is to partially replace concrete with steel chips. Due to these factors and the abundance of material, steel chips were used as a partial cement replacement at 0.5%, 1%, 1.5%, and 2% by the volume of cement. The properties such as compressive strength, split tensile strength, flexural beam strength, and modulus of elasticity are checked after 7, 14, and 28 days. Comparing these qualities to those of control molds showed that by raising the percentage of steel chips in the concrete up to 1.5%, mechanical characteristics are improved; however, when the percentage is increased to 2%, mechanical properties are also affected

Exploring the biological and chemical complexity of the ligases.

Using a novel method to map and cluster chemical reactions, we have re-examined the chemistry of the ligases [Enzyme Commission (EC) Class 6] and their associated protein families in detail. The type of bond formed by the ligase can be automatically extracted from the equation of the reaction, replicating the EC subclass division. However, this subclass division hides considerable complexities, especially for the C-N forming ligases, which fall into at least three distinct types. The lower levels of the EC classification for ligases are somewhat arbitrary in their definition and add little to understanding their chemistry or evolution. By comparing the multi-domain architecture of the enzymes and using sequence similarity networks, we examined the links between overall reaction and evolution of the ligases. These show that, whilst many enzymes that perform the same overall chemistry group together, both convergent (similar function, different ancestral lineage) and divergent (different function, common ancestor) evolution of function are observed. However, a common theme is that a single conserved domain (often the nucleoside triphosphate binding domain) is combined with ancillary domains that provide the variation in substrate binding and function

The Classification and Evolution of Enzyme Function.

Enzymes are the proteins responsible for the catalysis of life. Enzymes sharing a common ancestor as defined by sequence and structure similarity are grouped into families and superfamilies. The molecular function of enzymes is defined as their ability to catalyze biochemical reactions; it is manually classified by the Enzyme Commission and robust approaches to quantitatively compare catalytic reactions are just beginning to appear. Here, we present an overview of studies at the interface of the evolution and function of enzymes

DOES WORKING CAPITAL MANAGEMENT AFFECT CORPORATE PROFITABILITY?

Managing working capital efficiently and effectively is critical for modern organizations as it directly affects firm’s profitability, liquidity and riskiness. A vast majority of empirical studies have focused on developed countries whereas in case of developing countries like Pakistan it is somewhat under researched. The economy of Pakistan is passing through challenging times with rising inflation, energy crisis, poor law and order etc. Therefore, the purpose of the study was to investigate whether working capital policies adopted by listed organizations within the sugar industry of Pakistan (PSX) are efficient or not in these challenging conditions and what kind of effect (positive or negative) they have on the profitability of the firm. Data from 2006 to 2015 was collected for this study and Ordinary Least Squares (OLS) technique was used to analyse the effect of working capital management on firm profitability. Empirical results of the study show that all four components of working capital used in this study have statistically significant and negative relationship with firm’s profitability.Â

The evolution of enzyme function in the isomerases.

The advent of computational approaches to measure functional similarity between enzymes adds a new dimension to existing evolutionary studies based on sequence and structure. This paper reviews research efforts aiming to understand the evolution of enzyme function in superfamilies, presenting a novel strategy to provide an overview of the evolution of enzymes belonging to an individual EC class, using the isomerases as an exemplar

DOES WORKING CAPITAL MANAGEMENT AFFECT CORPORATE PROFITABILITY?

Managing working capital efficiently and effectively is critical for modern organizations as it directly affects firm’s profitability, liquidity and riskiness. A vast majority of empirical studies have focused on developed countries whereas in case of developing countries like Pakistan it is somewhat under researched. The economy of Pakistan is passing through challenging times with rising inflation, energy crisis, poor law and order etc. Therefore, the purpose of the study was to investigate whether working capital policies adopted by listed organizations within the sugar industry of Pakistan (PSX) are efficient or not in these challenging conditions and what kind of effect (positive or negative) they have on the profitability of the firm. Data from 2006 to 2015 was collected for this study and Ordinary Least Squares (OLS) technique was used to analyse the effect of working capital management on firm profitability. Empirical results of the study show that all four components of working capital used in this study have statistically significant and negative relationship with firm’s profitability.

Genomes of <i>Helicobacter pylori</i> from native Peruvians suggest admixture of ancestral and modern lineages and reveal a western type cag-pathogenicity island

Background: Helicobacter pylori is presumed to be co-evolved with its human host and is a highly diverse gastric pathogen at genetic levels. Ancient origins of H. pylori in the New World are still debatable. It is not clear how different waves of human migrations in South America contributed to the evolution of strain diversity of H. pylori. The objective of our 'phylogeographic' study was to gain fresh insights into these issues through mapping genetic origins of H. pylori of native Peruvians (of Amerindian ancestry) and their genomic comparison with isolates from Spain, and Japan. Results: For this purpose, we attempted to dissect genetic identity of strains by fluorescent amplified fragment length polymorphism (FAFLP) analysis, multilocus sequence typing (MLST) of the 7 housekeeping genes (atpA, efp, ureI, ppa, mutY, trpC, yphC) and the sequence analyses of the babB adhesin and oipA genes. The whole cag pathogenicity-island (cagPAI) from these strains was analyzed using PCR and the geographic type of cagA phosphorylation motif EPIYA was determined by gene sequencing. We observed that while European genotype (hp-Europe) predominates in native Peruvian strains, approximately 20% of these strains represent a sub-population with an Amerindian ancestry (hsp-Amerind). All of these strains however, irrespective of their ancestral affiliation harbored a complete, 'western' type cagPAI and the motifs surrounding it. This indicates a possible acquisition of cagPAI by the hsp-Amerind strains from the European strains, during decades of co-colonization. Conclusion: Our observations suggest presence of ancestral H. pylori (hsp-Amerind) in Peruvian Amerindians which possibly managed to survive and compete against the Spanish strains that arrived to the New World about 500 years ago. We suggest that this might have happened after native Peruvian H. pylori strains acquired cagPAI sequences, either by new acquisition in cagnegative strains or by recombination in cag positive Amerindian strains

Mucosal genomics implicate lymphocyte activation and lipid metabolism in refractory environmental enteric dysfunction

Background & aims: Environmental enteric dysfunction (EED) limits the Sustainable Development Goals of improved childhood growth and survival. We applied mucosal genomics to advance our understanding of EED.Methods: The Study of Environmental Enteropathy and Malnutrition (SEEM) followed 416 children from birth to 24 months in a rural district in Pakistan. Biomarkers were measured at 9 months and tested for association with growth at 24 months. The duodenal methylome and transcriptome was determined in 52 undernourished SEEM participants and 42 North American controls and celiac disease patients.Results: After accounting for growth at study entry, circulating IGF-1 and ferritin predicted linear growth, whereas leptin correlated with future weight gain. The EED transcriptome exhibited suppression of antioxidant, detoxification, and lipid metabolism genes, and induction of anti-microbial response, interferon, and lymphocyte activation genes. Relative to celiac disease, suppression of antioxidant and detoxification genes and induction of anti-microbial response genes were EED-specific. At the epigenetic level, EED showed hyper-methylation of epithelial metabolism and barrier function genes, and hypo-methylation of immune response and cell proliferation genes. Duodenal co-expression modules showed association between lymphocyte proliferation and epithelial metabolic genes and histologic severity, fecal energy loss, and wasting (weight-for-length/height Z\u3c-2.0). Leptin was associated with expression of epithelial carbohydrate metabolism and stem cell renewal genes. Immune response genes were attenuated by giardia colonization.Conclusions: Children with reduced circulating IGF-1 are more likely to experience stunting. Leptin and a gene signature for lymphocyte activation and dysregulated lipid metabolism are implicated in wasting, suggesting new approaches for EED refractory to nutritional intervention

Genomes of Helicobacter pylori from native Peruvians suggest admixture of ancestral and modern lineages and reveal a western type cag-pathogenicity island

BACKGROUND: Helicobacter pylori is presumed to be co-evolved with its human host and is a highly diverse gastric pathogen at genetic levels. Ancient origins of H. pylori in the New World are still debatable. It is not clear how different waves of human migrations in South America contributed to the evolution of strain diversity of H. pylori. The objective of our 'phylogeographic' study was to gain fresh insights into these issues through mapping genetic origins of H. pylori of native Peruvians (of Amerindian ancestry) and their genomic comparison with isolates from Spain, and Japan. RESULTS: For this purpose, we attempted to dissect genetic identity of strains by fluorescent amplified fragment length polymorphism (FAFLP) analysis, multilocus sequence typing (MLST) of the 7 housekeeping genes (atpA, efp, ureI, ppa, mutY, trpC, yphC) and the sequence analyses of the babB adhesin and oipA genes. The whole cag pathogenicity-island (cagPAI) from these strains was analyzed using PCR and the geographic type of cagA phosphorylation motif EPIYA was determined by gene sequencing. We observed that while European genotype (hp-Europe) predominates in native Peruvian strains, approximately 20% of these strains represent a sub-population with an Amerindian ancestry (hsp-Amerind). All of these strains however, irrespective of their ancestral affiliation harbored a complete, 'western' type cagPAI and the motifs surrounding it. This indicates a possible acquisition of cagPAI by the hsp-Amerind strains from the European strains, during decades of co-colonization. CONCLUSION: Our observations suggest presence of ancestral H. pylori (hsp-Amerind) in Peruvian Amerindians which possibly managed to survive and compete against the Spanish strains that arrived to the New World about 500 years ago. We suggest that this might have happened after native Peruvian H. pylori strains acquired cagPAI sequences, either by new acquisition in cag-negative strains or by recombination in cag positive Amerindian strains