Proteomic characterization of HIV-modulated membrane receptors, kinases and signaling proteins involved in novel angiogenic pathways

<p>Abstract</p> <p>Background</p> <p>Kaposi's sarcoma (KS), hemangioma, and other angioproliferative diseases are highly prevalent in HIV-infected individuals. While KS is etiologically linked to the human herpesvirus-8 (HHV8) infection, HIV-patients without HHV-8 and those infected with unrelated viruses also develop angiopathies. Further, HIV-Tat can activate protein-tyrosine-kinase (PTK-activity) of the vascular endothelial growth factor receptor involved in stimulating angiogenic processes. However, Tat by itself or HHV8-genes alone cannot induce angiogenesis <it>in vivo </it>unless specific proteins/enzymes are produced synchronously by different cell-types. We therefore tested a hypothesis that <it>chronic </it>HIV-<it>replication in non-endothelial cells </it>may produce novel factors that provoke angiogenic pathways.</p> <p>Methods</p> <p>Genome-wide proteins from HIV-infected and uninfected T-lymphocytes were tested by subtractive proteomics analyses at various stages of virus and cell growth <it>in vitro </it>over a period of two years. Several thousand differentially regulated proteins were identified by mass spectrometry (MS) and >200 proteins were confirmed in multiple gels. Each protein was scrutinized extensively by protein-interaction-pathways, bioinformatics, and statistical analyses.</p> <p>Results</p> <p>By functional categorization, 31 proteins were identified to be associated with various signaling events involved in angiogenesis. 88% proteins were located in the plasma membrane or extracellular matrix and >90% were found to be essential for regeneration, neovascularization and angiogenic processes during embryonic development.</p> <p>Conclusion</p> <p>Chronic HIV-infection of T-cells produces membrane receptor-PTKs, serine-threonine kinases, growth factors, adhesion molecules and many diffusible signaling proteins that have not been previously reported in HIV-infected cells. Each protein has been associated with endothelial cell-growth, morphogenesis, sprouting, microvessel-formation and other biological processes involved in angiogenesis (p = 10^-4to 10^-12). Bioinformatics analyses suggest that overproduction of PTKs and other kinases in HIV-infected cells has <it>suppressed </it>VEGF/VEGFR-PTK expression and promoted <it>VEGFR-independent </it>pathways. This unique mechanism is similar to that observed in neovascularization and angiogenesis during embryogenesis. Validation of clinically relevant proteins by gene-silencing and translational studies <it>in vivo </it>would identify specific targets that can be used for early diagnosis of angiogenic disorders and future development of inhibitors of angiopathies. This is the first comprehensive study to demonstrate that HIV-infection alone, without any co-infection or treatment, can induce numerous "embryonic" proteins and kinases capable of generating novel <it>VEGF-independent </it>angiogenic pathways.</p

Analytical models for pick distances in fishbone warehouse based on exact distance contour

The pick distance models for a unit load warehouse employing fishbone layout conventionally use semicircular approximation for distance contour which can result in significant error. This paper develops discrete and continuous pick distance models for fishbone layout under random, full turnover, and class-based storage policies based on exact polygonal distance contour. Class-based storage policy with three classes was found to give pick distance comparable to full turnover policy over a range of demand skews and warehouse shapes studied. The discrete and continuous models are compared considering finite storage space, aisle width and discontinues in the ABC curve for a real life data. The sensitivity of warehouse performance over a range of warehouse parameters is studied. We also outline a methodology for class-based storage design where class partitions can be derived for a warehouse of any dimension from the results of a unit area warehouse

Analytical models for a new turnover-based hybrid storage policy in unit-load warehouses

This paper considers a low-level unit-load warehouse employing single-deep storage lanes and a single-command manual storage and retrieval policy. Analytical travel distance models are developed for class-based and full turnover storage policies under across-aisle, within-aisle and a newly proposed hybrid product placement schemes. Our computational studies show that the analytical models developed in this paper are very accurate as compared to simulation results and a comparative study with a real-world warehouse case. Hybrid storage policies proposed in this paper outperform all other traditional storage policies. The paper also presents insights and simple design rules to warehouse practitioners

Class-Based Storage Assignment in a Unit-Load Warehouse Employing AS/RS with Inventory Space Allocation Considering Product Specific Setup to Holding Cost Ratio

Many authors have used continuous optimization models for class-based storage allocation for unit load warehouses employing AS/RS system assuming the same setup to holding cost ratio for all products in their EOQ inventory policy. Accordingly, an ABC curve based on demand ordering of products is used to determine pallet turnovers in their travel distance models which is not applicable in many practical situations and can be inaccurate. This paper develops a new model to determine two/three class optimal partitions while relaxing assumption of constant setup to holding cost ratio in the EOQ formula and as a consequence uses an ABC curve based on decreasing ranking of product turnovers rather than that based on demand. Computational experience shows that this new continuous model approximates pick travel distances which are very close to as compared to that of a semi-discrete model (SDM) proposed in this paper. Further computational experiments are also provided comparing traditional models with our formulations

Aggregate and detailed production planning integrating procurement and distribution plans in a multi-site environment

A monolithic mixed integer linear goal programming (MILGP) model that is developed in this paper produces a time and capacity aggregated production plan, a detailed production plan, a detailed procurement plan and a detailed distribution plan simultaneously to overcome the drawbacks of the hierarchical/sequential planning approaches of not yielding a feasible and/or an optimal plan. The model uses different time-grids and planning horizons for aggregate and detailed planning to reduce the computational burden. The limitations of storage space, raw material availability and production capacity at plants and a requirement of maintaining a minimum level of inventory buffer or forward cover have been modelled. Two heuristics that are proposed to solve the MILGP model gave good quality solutions with an average and the worse case optimality gap of 1.17% and 4.4% respectively when applied to one hundred randomly generated industry size problem instances

Efficient algorithm for cell formation with sequence data, machine replications and alternative process routings

Cell formation is an important problem in the design of a cellular manufacturing system. Despite a large number of papers on cell formation being published, only a handful incorporate operation sequence in intercell move calculations and consider alternative process routings, cell size, production volume and allocating units of identical machines into different cells. Modelling the above factors makes the cell formation problem complex but more realistic. The paper develops a model and solution methodology for a problem of cell formation to minimize the sum of costs of intercell moves, machine investment and machine operating costs considering all the factors mentioned above. An algorithm comprised of simulated annealing and local search heuristics has been developed to solve the model. A limited comparison of the proposed algorithm with an optimal solution generated by complete enumeration of small problems indicates that the algorithm produces a solution of excellent quality. Large problems with 100 parts and 50 machine types are efficiently solved using the algorithm

Design of an order-picking warehouse factoring vertical travel and space sharing

This paper considers the layout design problem of a single block order-picking rack-based warehouse that employs turnover-based storage assignment in both vertical and horizontal dimensions. An analytical expression for vertical travel distance is derived which is incorporated in the pick distance model. The effect of inventory staggering on storage space requirement is considered in arriving at warehouse dimensions. A model that incorporates area cost along with handling cost in optimizing warehouse design is developed and a solution algorithm is presented. The analytical model for vertical travel and the optimization model are applied to data from a real life case. It was found that the model would offer considerable operational cost savings, especially when space costs are high. Computational experiments show that the effect of inventory staggering is quite significant in the estimated storage space. Experiments also demonstrated the importance of segregating products based on turnover in the vertical dimension

Class-based storage-location assignment to minimise pick travel distance

Storage-location assignment in warehouses is an important task as it impacts productivity of other warehouse processes. The class-based storage policy distributes the products, among a number of classes, and for each class it reserves a region within the storage area. We propose a nonlinear integer-programming model to the problem of formation of classes and allocation of storage space, considering savings in required storage space, due to random allocation of products within a class. We develop a branch and bound algorithm (BBA) to solve the model and compare it with a benchmark dynamic programming algorithm (DPA). These algorithms are applied to randomly generated data sets and to an industrial case. Computational experience shows that class-based policy can result in shorter pick-travel distances than the dedicated policy. The proposed BBA is found to be computationally much more efficient than DPA

Efficient formation of storage classes for warehouse storage location assignment: A simulated annealing approach

Class-based storage policy distributes products among a number of classes and for each class it reserves a region within the storage area. The procedures reported in the literature for formation of storage classes primarily consider order-picking cost ignoring storage-space cost. Moreover, in these procedures items are ordered on the basis of their cube per order index (COI), and items are then partitioned into classes maintaining this ordering. This excludes many possible product combinations in forming classes which may result in inferior solutions. In this paper, a simulated annealing algorithm (SAA) is developed to solve an integer programming model for class formation and storage assignment that considers all possible product combinations, storage-space cost and order-picking cost. Computational experience on randomly generated data sets and an industrial case shows that SAA gives superior results than the benchmark dynamic programming algorithm for class formation with COI ordering restriction. (c) 200

Forming GT cells incrementally using GRASP

Most research in cell design assumes that the entire plant is converted into group technology cells at once. However, empirical findings in recent papers suggest otherwise, that is, most industries have converted only part of the plant into manufacturing cells and most cells in industries are created and implemented sequentially over time. In this paper, we develop a mathematical model and a heuristic approach based on greedy random adaptive search procedures (GRASP) to address incremental cell formation problem. The methodology allows forming cells gradually and converting a fraction of the plant into cells