Second order optimization for the inference of gene regulatory pathways.

With the increasing availability of experimental data on gene interactions, modeling of gene regulatory pathways has gained special attention. Gradient descent algorithms have been widely used for regression and classification applications. Unfortunately, results obtained after training a model by gradient descent are often highly variable. In this paper, we present a new second order learning rule based on the Newton's method for inferring optimal gene regulatory pathways. Unlike the gradient descent method, the proposed optimization rule is independent of the learning parameter. The flow vectors are estimated based on biomass conservation. A set of constraints is formulated incorporating weighting coefficients. The method calculates the maximal expression of the target gene starting from a given initial gene through these weighting coefficients. Our algorithm has been benchmarked and validated on certain types of functions and on some gene regulatory networks, gathered from literature. The proposed method has been found to perform better than the gradient descent learning. Extensive performance comparison with the extreme pathway analysis method has underlined the effectiveness of our proposed methodology.

Nanocrystalline cellulose as a reinforcing agent for poly (vinyl alcohol)/ gellan-gum-based composite film for moxifloxacin ocular delivery.

Nanocrystalline cellulose (NCC) is a star material in drug delivery applications due to its good biocompatibility, large specific surface area, high tensile strength (TS), and high hydrophilicity. Poly(Vinyl Alcohol)/Gellan-gum-based innovative composite film has been prepared using nanocrystalline cellulose (PVA/GG/NCC) as a strengthening agent for ocular delivery of moxifloxacin (MOX) via solvent casting method. Impedance analysis was studied using the capacitive sensing technique for examining new capacitance nature of the nanocomposite MOX film. Antimicrobial properties of films were evaluated using Pseudomonas aeruginosa and Staphylococcus aureus as gram-negative and gram-positive bacteria respectively by disc diffusion technique. XRD revealed the characteristic peak of NCC and the amorphous form of the drug. Sustained in vitro release and enhanced corneal permeation of drug were noticed in the presence of NCC. Polymer matrix enhanced the mechanical properties (tensile strength 22.05 to 28.41 MPa) and impedance behavior (resistance 59.23 to 213.23 Ω) in the film due to the presence of NCC rather than its absence (16.78 MPa and 39.03 Ω respectively). Occurrence of NCC brought about good antimicrobial behavior (both gram-positive and gram-negative) of the film. NCC incorporated poly(vinyl alcohol)/gellan-gum-based composite film exhibited increased mechanical properties and impedance behavior for improved ocular delivery of moxifloxacin.

Development of eutectics of pioglitazone with citric acid and its effect on crystallite properties and dissolution.

Eutectics of pioglitazone were developed using citric acid (CA) as the co-former, and the effect on crystallite properties and dissolution has correspondingly been studied. Pioglitazone-citric acid eutectics (PC1, PC2, PC3, and PC4) in different molar ratios (3:1, 3:2, 1:1, and 3:4 respectively) were prepared by simple solvent evaporation method. Difference in dislocation density and strain value of the eutectics were observed, and the maximum strain value of PC1 might be due to the highest deformation activity compared to PC2, PC3, and PC4. Carbonyl-thiazolidine or carboxyl-pyridine weak bond formation might be the reason of producing eutectics of PGZ-CA rather than cocrystal with a docking score of - 2.2 Kcal/M. Likewise, lowest particle size was found with PC1 rather than that of pure PGZ and other eutectics. PC1 demonstrated highest dissolution of drug (68 %) rather than other eutectics (54 to 61 %) and PGZ (44 %) after 360 min.

An optimization rule for in silico identification of targeted overproduction in metabolic pathways.

In an extension of previous work, here we introduce a second-order optimization method for determining optimal paths from the substrate to a target product of a metabolic network, through which the amount of the target is maximum. An objective function for the said purpose, along with certain linear constraints, is considered and minimized. The basis vectors spanning the null space of the stoichiometric matrix, depicting the metabolic network, are computed, and their convex combinations satisfying the constraints are considered as flux vectors. A set of other constraints, incorporating weighting coefficients corresponding to the enzymes in the pathway, are considered. These weighting coefficients appear in the objective function to be minimized. During minimization, the values of these weighting coefficients are estimated and learned. These values, on minimization, represent an optimal pathway, depicting optimal enzyme concentrations, leading to overproduction of the target. The results on various networks demonstrate the usefulness of the methodology in the domain of metabolic engineering. A comparison with the standard gradient descent and the extreme pathway analysis technique is also performed. Unlike the gradient descent method, the present method, being independent of the learning parameter, exhibits improved results.

Gradient descent optimization in gene regulatory pathways.

BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example.

Incorporation of enzyme concentrations into FBA and identification of optimal metabolic pathways.

BACKGROUND: In the present article, we propose a method for determining optimal metabolic pathways in terms of the level of concentration of the enzymes catalyzing various reactions in the entire metabolic network. The method, first of all, generates data on reaction fluxes in a pathway based on steady state condition. A set of constraints is formulated incorporating weighting coefficients corresponding to concentration of enzymes catalyzing reactions in the pathway. Finally, the rate of yield of the target metabolite, starting with a given substrate, is maximized in order to identify an optimal pathway through these weighting coefficients. RESULTS: The effectiveness of the present method is demonstrated on two synthetic systems existing in the literature, two pentose phosphate, two glycolytic pathways, core carbon metabolism and a large network of carotenoid biosynthesis pathway of various organisms belonging to different phylogeny. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. Biological relevance and validation of the results are provided. Finally, the impact of the method on metabolic engineering is explained with a few examples. CONCLUSIONS: The method may be viewed as determining an optimal set of enzymes that is required to get an optimal metabolic pathway. Although it is a simple one, it has been able to identify a carotenoid biosynthesis pathway and the optimal pathway of core carbon metabolic network that is closer to some earlier investigations than that obtained by the extreme pathway analysis. Moreover, the present method has identified correctly optimal pathways for pentose phosphate and glycolytic pathways. It has been mentioned using some examples how the method can suitably be used in the context of metabolic engineering.