Analysis of Artificial Neural Networks For Building Automated Surrogate Algorithms

While attaining the objective of online optimization of complex chemical processes, the possibility of using the first principle based models is rarely an option, since such models demand large computational time. Surrogate models, which can emulate first principle based models, offer a credible solution to this problem, by ensuring faster optimization. Thus, the entire challenge of enabling online optimization of complex models depends on construction of efficient surrogate models. Often, the surrogate building algorithms have certain parameters that are usually fixed based on some heuristic, thereby inviting potential errors in building such surrogate models. This work aims at presenting an elaborate study on the effect of various parameters affecting the predictability of artificial neural networks viz.(a) architecture of ANN, (b) sample size required by the ANN, (c) maximum possible accuracy of prediction, (d) a robust sampling plan and (e) transfer function choice for node activation. The ANNs are then utilized as surrogates for a highly nonlinear industrial sintering process, the optimization of which is then realized nearly 7 times faster than the optimization study using the expensive phenomenological model

A Study of Concurrency Bugs and Advanced Development Support for Actor-based Programs

The actor model is an attractive foundation for developing concurrent applications because actors are isolated concurrent entities that communicate through asynchronous messages and do not share state. Thereby, they avoid concurrency bugs such as data races, but are not immune to concurrency bugs in general. This study taxonomizes concurrency bugs in actor-based programs reported in literature. Furthermore, it analyzes the bugs to identify the patterns causing them as well as their observable behavior. Based on this taxonomy, we further analyze the literature and find that current approaches to static analysis and testing focus on communication deadlocks and message protocol violations. However, they do not provide solutions to identify livelocks and behavioral deadlocks. The insights obtained in this study can be used to improve debugging support for actor-based programs with new debugging techniques to identify the root cause of complex concurrency bugs.Comment: - Submitted for review - Removed section 6 "Research Roadmap for Debuggers", its content was summarized in the Future Work section - Added references for section 1, section 3, section 4.3 and section 5.1 - Updated citation

Dominant-Negative Loss of PPAR Function Enhances Smooth Muscle Cell Proliferation, Migration, and Vascular Remodeling

The Peroxisome Proliferator Activated Receptor-gamma (PPARγ) protein is a nuclear transcriptional activator with importance in diabetes management as the molecular target for the thiazolidinedione (TZD) family of drugs. Substantial evidence indicates that the TZD family of PPARγ agonists may retard the development of atherosclerosis. However, recent clinical data has suggested that at least one TZD may increase the risk of myocardial infarction and death from cardiovascular disease. In this study, we used a genetic approach to disrupt PPARγ signaling to probe the protein's role in smooth muscle cell (SMC) responses that are important for atherosclerosis

Metabolic Effects of Acute Thiamine Depletion Are Reversed by Rapamycin in Breast and Leukemia Cells

Thiamine-dependent enzymes (TDEs) control metabolic pathways that are frequently altered in cancer and therefore present cancer-relevant targets. We have previously shown that the recombinant enzyme thiaminase cleaves and depletes intracellular thiamine, has growth inhibitory activity against leukemia and breast cancer cell lines, and that its growth inhibitory effects were reversed in leukemia cell lines by rapamycin. Now, we first show further evidence of thiaminase therapeutic potential by demonstrating its activity against breast and leukemia xenografts, and against a primary leukemia xenograft. We therefore further explored the metabolic effects of thiaminase in combination with rapamycin in leukemia and breast cell lines. Thiaminase decreased oxygen consumption rate and increased extracellular acidification rate, consistent with the inhibitory effect of acute thiamine depletion on the activity of the TDEs pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes; these effects were reversed by rapamycin. Metabolomic studies demonstrated intracellular thiamine depletion and the presence of the thiazole cleavage product in thiaminase-treated cells, providing validation of the experimental procedures. Accumulation of ribose and ribulose in both cell lines support the thiaminase-mediated suppression of the TDE transketolase. Interestingly, thiaminase suppression of another TDE, branched chain amino ketoacid dehydrogenase (BCKDH), showed very different patterns in the two cell lines: in RS4 leukemia cells it led to an increase in BCKDH substrates, and in MCF-7 breast cancer cells it led to a decrease in BCKDH products. Immunoblot analyses showed corresponding differences in expression of BCKDH pathway enzymes, and partial protection of thiaminase growth inhibition by gabapentin indicated that BCKDH inhibition may be a mechanism of thiaminase-mediated toxicity. Surprisingly, most of thiaminase-mediated metabolomic effects were also reversed by rapamycin. Thus, these studies demonstrate that acute intracellular thiamine depletion by recombinant thiaminase results in metabolic changes in thiamine-dependent metabolism, and demonstrate a previously unrecognized role of mTOR signaling in the regulation of thiamine-dependent metabolism

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses

Lysophosphatidic Acid Receptors 1 and 2 Play Roles in Regulation of Vascular Injury Responses but Not Blood Pressure

Phenotypic modulation of vascular smooth muscle cells (SMC) is essential for the development of intimal hyperplasia. Lysophosphatidic acid (LPA) is a serum component that can promote phenotypic modulation of cultured SMC, but an endogenous role for this bioactive lipid as a regulator of SMC function in vivo has not been established. Ligation injury of the carotid artery in mice increased levels in the vessel of both autotaxin, the lysophospholipaseD enzyme responsible for generation of extracellular LPA, and two LPA responsive G-protein coupled receptors 1 (LPA1) and 2 (LPA2). LPA1-/-2-/- mice were partially protected from the development of injury-induced neointimal hyperplasia, whereas LPA1-/- mice developed larger neointimal lesions after injury. Growth in serum, LPA-induced ERK activation, and migration to LPA and serum were all attenuated in SMC isolated from LPA1-/-2-/- mice. In contrast, LPA1-/- SMCs exhibited enhanced migration resulting from an upregulation of LPA3. However, despite their involvement in intimal hyperplasia, neither LPA1 nor LPA2 were required for dedifferentiation of SMC following vascular injury or dedifferentiation of isolated SMC in response to LPA or serum in vitro. Similarly, neither LPA1 nor LPA2 were required for LPA to elicit a transient increase in blood pressure following intravenous administration of LPA to mice. These results identify a role for LPA and two defined LPA receptors in regulating SMC migratory responses in the context of vascular injury, but suggest that additional LPA receptor subtypes are required for other LPA-mediated effects in the vasculature

Fine mapping and sequence analysis reveal a promising candidate gene encoding a novel NB-ARC domain derived from wild rice (Oryza officinalis) that confers bacterial blight resistance

Bacterial blight disease of rice caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most serious constraints in rice production. The most sustainable strategy to combat the disease is the deployment of host plant resistance. Earlier, we identified an introgression line, IR 75084-15-3-B-B, derived from Oryza officinalis possessing broad-spectrum resistance against Xoo. In order to understand the inheritance of resistance in the O. officinalis accession and identify genomic region(s) associated with resistance, a recombinant inbred line (RIL) mapping population was developed from the cross Samba Mahsuri (susceptible to bacterial blight) × IR 75084-15-3-B-B (resistant to bacterial blight). The F2 population derived from the cross segregated in a phenotypic ratio of 3: 1 (resistant susceptible) implying that resistance in IR 75084-15-3-B-B is controlled by a single dominant gene/quantitative trait locus (QTL). In the F7 generation, a set of 47 homozygous resistant lines and 47 homozygous susceptible lines was used to study the association between phenotypic data obtained through screening with Xoo and genotypic data obtained through analysis of 7K rice single-nucleotide polymorphism (SNP) chip. Through composite interval mapping, a major locus was detected in the midst of two flanking SNP markers, viz., Chr11.27817978 and Chr11.27994133, on chromosome 11L with a logarithm of the odds (LOD) score of 10.21 and 35.93% of phenotypic variation, and the locus has been named Xa48t. In silico search in the genomic region between the two markers flanking Xa48t identified 10 putatively expressed genes located in the region of interest. The quantitative expression and DNA sequence analysis of these genes from contrasting parents identified the Os11g0687900 encoding an NB-ARC domain-containing protein as the most promising gene associated with resistance. Interestingly, a 16-bp insertion was noticed in the untranslated region (UTR) of the gene in the resistant parent, IR 75084-15-3-B-B, which was absent in Samba Mahsuri. The association of Os11g0687900 with resistance phenotype was further established by sequence-based DNA marker analysis in the RIL population. A co-segregating PCR-based INDEL marker, Marker_Xa48, has been developed for use in the marker-assisted breeding of Xa48t